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Lu L, Hua W, Li F, Che Z, Tian M, Lu YY, Chi Q, Zhang J, Huang Q. Arsenic Exposure Triggers Nonalcoholic Fatty Liver Disease through Repressing S-Adenosylmethionine-Dependent Histone Methylation in Rats. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:268-278. [PMID: 39746780 DOI: 10.1021/acs.est.4c10417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Arsenic (As) is a toxic metalloid widespread in the environment, and its exposure has been associated with a variety of adverse health outcomes. As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Fabp1, Srebf1, and Apoc3, while downregulated Acox1 and Cpt1a in rat liver. In addition, it was found that inorganic arsenite (iAsIII) was methylated to DMA, and the S-adenosylmethionine (SAM) level was decreased, which would contribute to the repression of H3K9me1/2 in rat liver after exposure. The in vitro studies revealed that SAM supplementation attenuated lipid accumulation by restoring H3K9me1/2 in HepG2 cells, which further confirmed our animal results. Therefore, it is suggested that As methylation depleted SAM, which inhibited H3K9me1/2 and activated Fabp1, Srebf1, and Apoc3 expressions, leading to NAFLD upon inorganic As exposure. Overall, these data shed new light on the role of SAM-mediated histone methylation in As-triggered NAFLD, which could be useful for the prevention and intervention of hepatotoxicity induced by environmental As exposure.
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Affiliation(s)
- Lu Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
- College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Weizhen Hua
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Fuping Li
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Zhenbin Che
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Meiping Tian
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Yan-Yang Lu
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Qiaoqiao Chi
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
| | - Jie Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Qingyu Huang
- Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China
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Almohawes ZN, El-Kott A, Morsy K, Shati AA, El-Kenawy AE, Khalifa HS, Elsaid FG, Abd-Lateif AEKM, Abu-Zaiton A, Ebealy ER, Abdel-Daim MM, Ghanem RA, Abd-Ella EM. Salidroside inhibits insulin resistance and hepatic steatosis by downregulating miR-21 and subsequent activation of AMPK and upregulation of PPARα in the liver and muscles of high fat diet-fed rats. Arch Physiol Biochem 2024; 130:257-274. [PMID: 35061559 DOI: 10.1080/13813455.2021.2024578] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/15/2021] [Accepted: 12/27/2021] [Indexed: 02/06/2023]
Abstract
This study evaluated if salidroside (SAL) alleviates high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) by downregulating miR-21. Rats (n = 8/group) were treated for 12 weeks as normal diet (control/ND), ND + agmoir negative control (NC) (150 µg/kg), ND + SAL (300 mg/kg), HFD, HFD + SAL, HFD + compound C (an AMPK inhibitor) (200 ng/kg), HFD + SAL + NXT629 (a PPAR-α antagonist) (30 mg/kg), and HFD + SAL + miR-21 agomir (150 µg/kg). SAL improved glucose and insulin tolerance and preserved livers in HFD-fed rats. In ND and HFD-fed rats, SAL reduced levels of serum and hepatic lipids and the hepatic expression of SREBP1, SREBP2, fatty acid (FA) synthase, and HMGCOAR. It also activated hepatic Nrf2 and increased hepatic/muscular activity of AMPK and levels of PPARα. All effects afforded by SAL were prevented by CC, NXT629, and miR-21 agmoir. In conclusion, activation of AMPK and upregulation of PPARα mediate the anti-steatotic effect of SAL.
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Affiliation(s)
- Zakiah N Almohawes
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Attalla El-Kott
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| | - Kareem Morsy
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, College of Science, Cairo University, Cairo, Egypt
| | - Ali A Shati
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Ayman E El-Kenawy
- Pathology Department, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Heba S Khalifa
- Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| | - Fahmy G Elsaid
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | | | | | - Eman R Ebealy
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Pharmaceutical Sciences Department, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Reham A Ghanem
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Gamasa, Egypt
| | - Eman M Abd-Ella
- Zoology Department, College of Science, Fayoum University, Fayoum, Egypt
- Biology Department, College of Science and Art, Al-Baha University, Al-Mandaq, Saudi Arabia
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3
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Tang R, Liu R, Zha H, Cheng Y, Ling Z, Li L. Gut microbiota induced epigenetic modifications in the non-alcoholic fatty liver disease pathogenesis. Eng Life Sci 2024; 24:2300016. [PMID: 38708414 PMCID: PMC11065334 DOI: 10.1002/elsc.202300016] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/29/2023] [Accepted: 05/22/2023] [Indexed: 05/07/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a growing global health concern that can lead to liver disease and cancer. It is characterized by an excessive accumulation of fat in the liver, unrelated to excessive alcohol consumption. Studies indicate that the gut microbiota-host crosstalk may play a causal role in NAFLD pathogenesis, with epigenetic modification serving as a key mechanism for regulating this interaction. In this review, we explore how the interplay between gut microbiota and the host epigenome impacts the development of NAFLD. Specifically, we discuss how gut microbiota-derived factors, such as lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), can modulate the DNA methylation and histone acetylation of genes associated with NAFLD, subsequently affecting lipid metabolism and immune homeostasis. Although the current literature suggests a link between gut microbiota and NAFLD development, our understanding of the molecular mechanisms and signaling pathways underlying this crosstalk remains limited. Therefore, more comprehensive epigenomic and multi-omic studies, including broader clinical and animal experiments, are needed to further explore the mechanisms linking the gut microbiota to NAFLD-associated genes. These studies are anticipated to improve microbial markers based on epigenetic strategies and provide novel insights into the pathogenesis of NAFLD, ultimately addressing a significant unmet clinical need.
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Affiliation(s)
- Ruiqi Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Rongrong Liu
- Center of Pediatric Hematology‐oncologyPediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang ProvinceNational Clinical Research Center for Child HealthChildren's HospitalZhejiang University School of MedicineHangzhouChina
| | - Hua Zha
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Yiwen Cheng
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Zongxin Ling
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
- Jinan Microecological Biomedicine Shandong LaboratoryJinanChina
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Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95:101231. [PMID: 38056058 DOI: 10.1016/j.mam.2023.101231] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
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Affiliation(s)
- Maurizio Parola
- Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine - Royal Free Hospital, London, NW32PF, United Kingdom.
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Zhu YL, Meng LL, Ma JH, Yuan X, Chen SW, Yi XR, Li XY, Wang Y, Tang YS, Xue M, Zhu MZ, Peng J, Lu XJ, Huang JZ, Song ZC, Wu C, Zheng KZ, Dai QQ, Huang F, Fang HS. Loss of LBP triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPβ- SCD activation in non-alcoholic fatty liver disease. Zool Res 2024; 45:79-94. [PMID: 38114435 PMCID: PMC10839665 DOI: 10.24272/j.issn.2095-8137.2023.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 08/24/2023] [Indexed: 12/21/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( LBP), but the underlying epigenetic mechanisms remain understudied. Herein, LBP -/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP -/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP -/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein β (C/EBPβ) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene SCD as potential regulators and therapeutic targets.
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Affiliation(s)
- Ya-Ling Zhu
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
- Laboratory Animal Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Lei-Lei Meng
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jin-Hu Ma
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xin Yuan
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Shu-Wen Chen
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xin-Rui Yi
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xin-Yu Li
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Yi Wang
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Yun-Shu Tang
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
- Laboratory Animal Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China
| | - Min Xue
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Mei-Zi Zhu
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jin Peng
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Xue-Jin Lu
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Jian-Zhen Huang
- College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi 330045, China
| | - Zi-Chen Song
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Chong Wu
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Ke-Zhong Zheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Qing-Qing Dai
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Fan Huang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China. E-mail:
| | - Hao-Shu Fang
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, China
- Laboratory Animal Research Center, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China. E-mail:
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6
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Bi H, Zhou B, Yang J, Lu Y, Mao F, Song Y. Whole-genome DNA methylation and gene expression profiling in the livers of mice with nonalcoholic steatohepatitis. Life Sci 2023; 329:121951. [PMID: 37473799 DOI: 10.1016/j.lfs.2023.121951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/22/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major causes of liver-related morbidity and mortality. It ranges simple steatosis to non-alcoholic steatohepatitis (NASH). Previous studies have shown that epigenetic factors, such as DNA methylation, can contribute to the development and progression of simple steatosis. However, the profiling of whole-genome DNA methylation remains poorly characterized in NASH. MAIN METHODS In this study, we established a mouse model of diet-induced NASH, by maintaining male mice on a high-fructose-high-cholesterol diet (HFHC), to generate hepatic steatosis, inflammation and injury. We profiled hepatic gene expression by RNA-Sequencing and locus-specific 5-methylcytosine level, using Whole Genome Bisulfite Sequencing (WGBS). KEY FINDINGS We identified >1000 differentially methylated regions in NASH versus control group, indicating that NASH diet could modulate the liver methylome. Furthermore, integrated analysis of methylome and transcriptome identified certain key methylated genes and pathways, which may be involved in steroid metabolism and inflammation response. The liver methylation levels of key genes especially Tgfb, Msn, Iqgap1, Cyba, Fcgr1 decreased, and their consequent increased expression may lead to NASH development. SIGNIFICANCE We found that HFHC diet-induced NASH could induces genome-wide differential DNA methylation changes. Thus, we proposed that DNA methylation profiles of genomes may be a useful signature of gene transcription and may play an important role in the development of NASH. We also screened and validated the changes of key genes, which may provide new perspectives for the mechanistic study of NASH in future.
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Affiliation(s)
- Hanqi Bi
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Bing Zhou
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialin Yang
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Mao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yuping Song
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China.
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Singla T, Muneshwar KN, Pathade AG, Yelne S. Hepatocytic Ballooning in Non-alcoholic Steatohepatitis: Bridging the Knowledge Gap and Charting Future Avenues. Cureus 2023; 15:e45884. [PMID: 37885505 PMCID: PMC10598508 DOI: 10.7759/cureus.45884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is emerging as a significant global health concern, characterized by hepatic lipid accumulation, inflammation, and hepatocellular injury. Hepatocytic ballooning, a histological feature of NASH, has gained prominence for its role in disease progression and potential as a therapeutic target. This review provides an overview of the current knowledge regarding hepatocytic ballooning in NASH, highlighting the key molecular and cellular mechanisms implicated in its development. We delve into the intricate interplay of metabolic dysregulation, oxidative stress, and lipid toxicity as drivers of hepatocytic ballooning, shedding light on the pathways responsible for its initiation and perpetuation. Furthermore, we explore the diagnostic challenges associated with hepatocytic ballooning and its significance as a prognostic indicator in NASH patients. While hepatocytic ballooning holds promise as a therapeutic target, this abstract discusses the various experimental and clinical approaches to ameliorate this histological hallmark. Potential interventions, including lifestyle modifications, pharmacological agents, and emerging therapies, are evaluated in terms of their efficacy and safety profiles. In conclusion, this review underscores the need to bridge the knowledge gap surrounding hepatocytic ballooning in NASH and emphasizes its importance in understanding disease pathogenesis and progression. By charting future research avenues and clinical strategies, we aspire to advance our comprehension of NASH and ultimately improve patient outcomes in this rapidly evolving field of hepatology.
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Affiliation(s)
- Tanvi Singla
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Komal N Muneshwar
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Aniket G Pathade
- Research and Development, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Seema Yelne
- Nursing, Shalinitai Meghe College of Nursing, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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8
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Thomsen KL, Eriksen PL, Kerbert AJC, De Chiara F, Jalan R, Vilstrup H. Role of ammonia in NAFLD: An unusual suspect. JHEP Rep 2023; 5:100780. [PMID: 37425212 PMCID: PMC10326708 DOI: 10.1016/j.jhepr.2023.100780] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 07/11/2023] Open
Abstract
Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body's only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials.
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Affiliation(s)
- Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
- UCL Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Annarein JC. Kerbert
- UCL Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Francesco De Chiara
- UCL Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Rajiv Jalan
- UCL Institute of Liver and Digestive Health, University College London, United Kingdom
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
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9
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Chen Y, Wang W, Morgan MP, Robson T, Annett S. Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets. Front Endocrinol (Lausanne) 2023; 14:1148934. [PMID: 37361533 PMCID: PMC10286797 DOI: 10.3389/fendo.2023.1148934] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/16/2023] [Indexed: 06/28/2023] Open
Abstract
Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.
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Affiliation(s)
- Yinshuang Chen
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Maria P. Morgan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
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10
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Sun Y, Zheng C, Li T, He X, Yang F, Guo W, Song J, Gao Y, Deng C, Huang X. GB1a Activates SIRT6 to Regulate Lipid Metabolism in Mouse Primary Hepatocytes. Int J Mol Sci 2023; 24:ijms24119540. [PMID: 37298491 DOI: 10.3390/ijms24119540] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/18/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Lipid accumulation, oxidative stress, and inflammation in hepatocytes are features of nonalcoholic fatty liver disease (NAFLD). Garcinia biflavonoid 1a (GB1a) is a natural product capable of hepatic protection. In this study, the effect of GB1a on anti-inflammatory, antioxidant, and regulation of the accumulation in HepG2 cells and mouse primary hepatocytes (MPHs) was investigated, and its regulatory mechanism was further explored. The result showed that GB1a reduced triglyceride (TG) content and lipid accumulation by regulating the expression of SREBP-1c and PPARα; GB1a reduced reactive oxygen species (ROS) and improved cellular oxidative stress to protect mitochondrial morphology by regulating genes Nrf2, HO-1, NQO1, and Keap1; and GB1a reduced the damage of hepatocytes by inhibiting the expression of inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) p65. The activities of GB1a were lost in liver SIRT6-specific knockout mouse primary hepatocytes (SIRT6-LKO MPHs). This indicated that activating SIRT6 was critical for GB1a to perform its activity, and GB1a acted as an agonist of SIRT6. It was speculated that GB1a may be a potential drug for NAFLD treatment.
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Affiliation(s)
- Yongzhi Sun
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Congmin Zheng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ting Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinqian He
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Fan Yang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Wenfeng Guo
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yong Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Changsheng Deng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinan Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Institute of Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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11
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Zheng C, Zheng Y, Chen X, Zhong X, Zheng X, Yang S, Zheng Z. α-NETA down-regulates CMKLR1 mRNA expression in ileum and prevents body weight gains collaborating with ERK inhibitor PD98059 in turn to alleviate hepatic steatosis in HFD-induced obese mice but no impact on ileal mucosal integrity and steatohepatitis progression. BMC Endocr Disord 2023; 23:9. [PMID: 36624417 PMCID: PMC9830776 DOI: 10.1186/s12902-023-01267-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Studies on chemerin/chemokine-like receptor-1 have mainly focused on adipose and liver with the intestinal tissues largely overlooked. In this study conducted on obese mice, we have explored: 1) CMKLR1 expression in the ileums; 2) CMKLR1 inhibitor α-NETA on body weight and intestinal mucosa integrity hence the impact on hepatic steatosis and pathway involved. METHODS Nineteen male C57BL/6 mice were randomly divided into five groups: normal diet group (ND), high-fat diet group (HFD), HFD + α-NETA group (NETA), HFD + PD98059 group (PD) and HFD + α-NETA + PD98059 group (NETA + PD). Mice were fed either with a chow diet or HFD for 12 weeks. At 12th week, mice of ND were put on the diet as before; mice of NETA received daily treatments of α-NETA (30 mg/kg) via gavage; mice of PD received daily treatment of PD98059 via tail vein injection; mice of NETA + PD received daily treatment of α-NETA + PD98059, all for another 4 weeks. At the time intervention ended, mice were sacrificed. The body weight, the liver pathologies were assessed. Ileal CMKLR1 mRNA was evaluated by rtPCR; ZO-1, ERK1/2 protein expression of ileal tissues by western blotting; liver TNF-α and serum endotoxin by Elisa. RESULTS More weight gains in mice of HFD than ND (37.90 ± 3.00 g) vs (24.47 ± 0.50 g), P = 0.002; α-NETA reduced the body weight (33.22 ± 1.90 g) vs (37.90 ± 3.00 g), P = 0.033; and further reduced by NETA + PD98059: (31.20 ± 1.74 g) vs (37.30 ± 4.05 g), P = 0.032. CMKLR1 mRNA expression was up-regulated in ileum in group HFD compared with ND and down-regulated by α-NETA. Steatosis was only alleviated in group PD + NETA with less weight gain. No impact of α-NETA on ileal ZO-1 or pERK with western blotting, and no endotoxin level changes were detected. TNF-α was higher in group HFD than in group ND, while no significant difference between other groups. CONCLUSIONS CMKLR1 mRNA was up-regulated in the ileum of obese mice and down-regulated by α-NETA along with a body weight control collaborating with ERK inhibitor PD98059. Steatosis was alleviated in a weight dependent way. α-NETA has no influence on intestinal mucosal integrity and no impact on steatohepatitis progression.
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Affiliation(s)
- Canbin Zheng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, Guangdong, China
| | - Yongping Zheng
- Department of Gastroenterology, Shantou Central Hospital, 114 Waima Road, Shantou, 515031, Guangdong, China.
| | - Xi Chen
- Department of Clinical Medicine Research Center, Shantou Central Hospital, Shantou, Guangdong, China
| | - Xianyang Zhong
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, Guangdong, China
| | - Xiaobin Zheng
- Department of Gastroenterology, Shantou Central Hospital, 114 Waima Road, Shantou, 515031, Guangdong, China
| | - Shuhui Yang
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, Guangdong, China
| | - Zihui Zheng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, Guangdong, China
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Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis. Exp Mol Med 2023; 55:143-157. [PMID: 36609599 PMCID: PMC9898513 DOI: 10.1038/s12276-022-00919-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/17/2022] [Accepted: 11/13/2022] [Indexed: 01/07/2023] Open
Abstract
Dynamic alteration of DNA methylation leads to various human diseases, including nonalcoholic fatty liver disease (NAFLD). Although C-Maf-inducing protein (Cmip) has been reported to be associated with NAFLD, its exact underlying mechanism remains unclear. Here, we aimed to elucidate this mechanism in NAFLD in vitro and in vivo. We first identified alterations in the methylation status of the Cmip intron 1 region in mouse liver tissues with high-fat high-sucrose diet-induced NAFLD. Knockdown of DNA methyltransferase (Dnmt) 1 significantly increased Cmip expression. Chromatin immunoprecipitation assays of AML12 cells treated with oleic and palmitic acid (OPA) revealed that Dnmt1 was dissociated and that methylation of H3K27me3 was significantly decreased in the Cmip intron 1 region. Conversely, the knockdown of Tet methylcytosine dioxygenase 2 (Tet2) decreased Cmip expression. Following OPA treatment, the CCCTC-binding factor (Ctcf) was recruited, and H3K4me3 was significantly hypermethylated. Intravenous Cmip siRNA injection ameliorated NAFLD pathogenic features in ob/ob mice. Additionally, Pparγ and Cd36 expression levels were dramatically decreased in the livers of ob/ob mice administered siCmip, and RNA sequencing revealed that Gbp2 was involved. Gbp2 knockdown also induced a decrease in Pparγ and Cd36 expression, resulting in the abrogation of fatty acid uptake into cells. Our data demonstrate that Cmip and Gbp2 expression levels are enhanced in human liver tissues bearing NAFLD features. We also show that Dnmt1-Trt2/Ctcf-mediated reversible modulation of Cmip methylation regulates the Gbp2-Pparγ-Cd36 signaling pathway, indicating the potential of Cmip as a novel therapeutic target for NAFLD.
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Bankole T, Winn H, Li Y. Dietary Impacts on Gestational Diabetes: Connection between Gut Microbiome and Epigenetic Mechanisms. Nutrients 2022; 14:nu14245269. [PMID: 36558427 PMCID: PMC9786016 DOI: 10.3390/nu14245269] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common obstetric complications due to an increased level of glucose intolerance during pregnancy. The prevalence of GDM increases due to the obesity epidemic. GDM is also associated with an increased risk of gestational hypertension and preeclampsia resulting in elevated maternal and perinatal morbidity and mortality. Diet is one of the most important environmental factors associated with etiology of GDM. Studies have shown that the consumption of certain bioactive diets and nutrients before and during pregnancy might have preventive effects against GDM leading to a healthy pregnancy outcome as well as beneficial metabolic outcomes later in the offspring's life. Gut microbiome as a biological ecosystem bridges the gap between human health and diseases through diets. Maternal diets affect maternal and fetal gut microbiome and metabolomics profiles, which consequently regulate the host epigenome, thus contributing to later-life metabolic health in both mother and offspring. This review discusses the current knowledge regarding how epigenetic mechanisms mediate the interaction between maternal bioactive diets, the gut microbiome and the metabolome leading to improved metabolic health in both mother and offspring.
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Affiliation(s)
- Taiwo Bankole
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA
| | - Hung Winn
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, MO 65212, USA
| | - Yuanyuan Li
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA
- Correspondence:
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Varghese DS, Alawathugoda TT, Sheikh MA, Challagandla AK, Emerald BS, Ansari SA. Developmental modeling of hepatogenesis using obese iPSCs-hepatocyte differentiation uncovers pathological features. Cell Death Dis 2022; 13:670. [PMID: 35915082 PMCID: PMC9343434 DOI: 10.1038/s41419-022-05125-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 01/21/2023]
Abstract
Obesity is a multigene disorder. However, in addition to genetic factors, environmental determinants also participate in developing obesity and related pathologies. Thus, obesity could be best described as a combination of genetic and environmental perturbations often having its origin during the early developmental period. Environmental factors such as energy-dense food and sedentary lifestyle are known to be associated with obesogenicity. However, the combinatorial effects of gene-environment interactions are not well understood. Understanding the role of multiple genetic variations leading to subtle gene expression changes is not practically possible in monogenic or high-fat-fed animal models of obesity. In contrast, human induced pluripotent stem cells (hiPSCs) from individuals with familial obesity or an obesogenic genotype could serve as a good model system. Herein, we have used hiPSCs generated from normal and genetically obese subjects and differentiated them into hepatocytes in cell culture. We show that hepatocytes from obese iPSCs store more lipids and show increased cell death than normal iPSCs. Whole transcriptome analyses in both normal and obese iPSCs treated with palmitate compared to control revealed LXR-RXR and hepatic fibrosis pathways were enriched among other pathways in obese iPSCs compared to normal iPSCs. Among other genes, increased CD36 and CAV1 expression and decreased expression of CES1 in obese iPSCs could have been responsible for excess lipid accumulation, resulting in differential expression of genes associated with hepatic fibrosis, a key feature of non-alcoholic fatty liver disease (NAFLD). Our results demonstrate that iPSCs derived from genetically obese subjects could serve as an excellent model to understand the effects of this multigene disorder on organ development and may uncover pathologies of NAFLD, which is highly associated with obesity.
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Affiliation(s)
- Divya Saro Varghese
- grid.43519.3a0000 0001 2193 6666Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Thilina T. Alawathugoda
- grid.43519.3a0000 0001 2193 6666Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Muhammad Abid Sheikh
- grid.43519.3a0000 0001 2193 6666Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Anil Kumar Challagandla
- grid.43519.3a0000 0001 2193 6666Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates
| | - Bright Starling Emerald
- grid.43519.3a0000 0001 2193 6666Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates ,grid.43519.3a0000 0001 2193 6666Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi UAE
| | - Suraiya A. Ansari
- grid.43519.3a0000 0001 2193 6666Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates ,grid.43519.3a0000 0001 2193 6666Zayed Center for Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi UAE
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Aljabban J, Rohr M, Syed S, Khorfan K, Borkowski V, Aljabban H, Segal M, Mukhtar M, Mohammed M, Panahiazar M, Hadley D, Spengler R, Spengler E. Transcriptome changes in stages of non-alcoholic fatty liver disease. World J Hepatol 2022; 14:1382-1397. [PMID: 36158924 PMCID: PMC9376779 DOI: 10.4254/wjh.v14.i7.1382] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/29/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a ‘multiple hit’ hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.
AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.
METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.
RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset.
CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno , Fresno, CA 93701, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Saint Kitts 1621, Cayon, Saint Kitts and Nevis
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94305, United States
| | - Dexter Hadley
- Department of Artificial Intelligence, Pathology, University of Central Florida College of Medicine , Orlando, FL 32827, United States
| | - Ryan Spengler
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Erin Spengler
- Department of Gastroenterology and Hepatology, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
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Marjani S, Nezhadali M, Hekmat A, Yeganeh MZ. Investigating Visfatin gene Polymorphism rs4730153 with Insulin Resistance and Non-Alcoholic Fatty Liver Diseases in Iranian Population. IRANIAN JOURNAL OF PUBLIC HEALTH 2022; 51:1143-1151. [PMID: 36407748 PMCID: PMC9643234 DOI: 10.18502/ijph.v51i5.9429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/23/2021] [Indexed: 06/16/2023]
Abstract
BACKGROUND Visfatin is known as one of the adipokines associated with the development of inflammation, but its role in the pathogenesis of nonalcoholic fatty liver is less known so far. We aimed to investigate the association between visfatin gene polymorphism rs4730153 and insulin resistance and non-alcoholic fatty liver disease (NAFLD). METHODS This case-control study was performed on 80 patients with NAFLD as well as 80 healthy participants as controls referred to Amir Al-Momenin and Bouali hospitals in Tehran. Genotyping was performed using PCR-RFLP method. Plasma concentrations of visfatin and insulin were measured using ELISA kit. The fasting blood glucose, TC, TG, LDL-C, HDL-C, ALT, AST, SBP, DBP, and BMI levels were measured using the standard methods. Statistical analysis was also performed using SPSS software. RESULTS A significant difference was found in Visfatin level in the patients with NAFLD compared to this level in healthy individuals. The levels of HDL-C and LDL-C in healthy individuals and triglyceride in patients for GG, AG, and AA genotypes carriers also were significantly different. There was a significant relationship between rs4730153 polymorphism and insulin resistance; however, no association was found between this polymorphism and NAFLD. Notably, Visfatin showed a significant association with age (all individuals), body mass index (healthy individuals), insulin, and HOMA (in patients). CONCLUSION Visfatin levels reduced in patients with NAFLD. Moreover, rs4730153 polymorphism was indicated to be associated with both lipid metabolism and insulin resistance, but no association was found between this polymorphism and nonalcoholic fatty liver disease.
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Affiliation(s)
- Somayeh Marjani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Masoumeh Nezhadali
- Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
| | - Azadeh Hekmat
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Marjan Zarif Yeganeh
- Cellular and Molecular Endocrine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Liver Steatosis: A Marker of Metabolic Risk in Children. Int J Mol Sci 2022; 23:ijms23094822. [PMID: 35563210 PMCID: PMC9100068 DOI: 10.3390/ijms23094822] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
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Liu J, Yang D, Wang X, Asare PT, Zhang Q, Na L, Shao L. Gut Microbiota Targeted Approach in the Management of Chronic Liver Diseases. Front Cell Infect Microbiol 2022; 12:774335. [PMID: 35444959 PMCID: PMC9014089 DOI: 10.3389/fcimb.2022.774335] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
The liver is directly connected to the intestines through the portal vein, which enables the gut microbiota and gut-derived products to influence liver health. There is accumulating evidence of decreased gut flora diversity and alcohol sensitivity in patients with various chronic liver diseases, including non-alcoholic/alcoholic liver disease, chronic hepatitis virus infection, primary sclerosing cholangitis and liver cirrhosis. Increased intestinal mucosal permeability and decline in barrier function were also found in these patients. Followed by bacteria translocation and endotoxin uptake, these will lead to systemic inflammation. Specific microbiota and microbiota-derived metabolites are altered in various chronic liver diseases studies, but the complex interaction between the gut microbiota and liver is missing. This review article discussed the bidirectional relationship between the gut and the liver, and explained the mechanisms of how the gut microbiota ecosystem alteration affects the pathogenesis of chronic liver diseases. We presented gut-microbiota targeted interventions that could be the new promising method to manage chronic liver diseases.
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Affiliation(s)
- Jing Liu
- Department of Research, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital; The College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Dakai Yang
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiaojing Wang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Paul Tetteh Asare
- Human and Animal Health Unit, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland
| | - Qingwen Zhang
- Department of Research, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital; The College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Lixin Na
- Department of Research, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital; The College of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Lei Shao
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
- *Correspondence: Lei Shao,
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Pan X, Wu Y, Peng H, Cai X, Hu Z, Lin X, Peng XE. Genome-wide DNA methylation profiling in nonalcoholic fatty liver reveals predictive aberrant methylation in PRKCE and SEC14L3 promoters. Dig Liver Dis 2022; 54:521-528. [PMID: 34108094 DOI: 10.1016/j.dld.2021.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Optimal non-invasive biomarkers for diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) remain to be identified. AIMS To identify potential DNA methylation biomarkers for NAFLD. METHODS Genome-wide DNA methylation profiling was performed to identify differentially methylated CpG sites in peripheral blood leukocytes. Differentially methylated regions were validated using the MassCLEAVE assay. The expression levels of candidate genes were explored by Gene Expression Omnibus database. RESULTS The hypomethylation of PRKCE CpG 4.5 and CpG 18.19 was associated with nonalcoholic fatty liver (NAFL), the odds ratio (OR) and 95% confidence interval (CI) were 0.129 (0.026-0.639) and 0.231 (0.069-0.768). The methylation level of CpG 1.2 and average methylation level of SEC14L3 were correlated with NAFL, with OR (95% CI) being 0.283 (0.093-0.865) and 0.264 (0.087-0.799). PRKCE CpG 4.5 and cg17802464 of SEC14L3 were correlated with body mass index, waist circumference, total triglyceride, high-density lipoprotein cholesterol, alanine aminotransferase and aspartate aminotransferase. All selected datasets showed high expression levels of PRKCE and SEC14L3 in patients with NAFLD. CONCLUSIONS Our findings suggest that the hypomethylation of PRKCE and SEC14L3 promoters represent attractive biomarkers for NAFLD. Further studies are warranted to validate these biomarkers as molecular tools for diagnosis of NAFLD and therapeutic targets.
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Affiliation(s)
- Xinting Pan
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China; The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, PR China
| | - Yunli Wu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China
| | - Hewei Peng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Xiaoling Cai
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Zhijian Hu
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China
| | - Xian-E Peng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, PR China.
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Cadmium Exposure in Young Adulthood Is Associated with Risk of Nonalcoholic Fatty Liver Disease in Midlife. Dig Dis Sci 2022; 67:689-696. [PMID: 33630217 PMCID: PMC8843233 DOI: 10.1007/s10620-021-06869-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 01/20/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Studies have suggested that cadmium (Cd) may be involved in the etiology of nonalcoholic fatty liver disease (NAFLD), but available data in human is sparse. AIMS We aimed to examine Cd exposure in young adulthood in relation to prevalent NAFLD in midlife among American adults. METHODS This study included 2446 participants from the Coronary Artery Risk Development in Young Adults study with toenail Cd measurement at exam year 2 (baseline) and computed tomography quantification of liver fat at exam year 25. Toenail Cd concentrations were considered as a reliable marker of long-term exposure. NAFLD was defined if liver attenuation < 51 Hounsfield units after excluding other possible causes of liver fat. Multivariable-adjusted logistic regression models were used to estimate the odds ratio of NAFLD by Cd exposure. RESULTS Median toenail Cd concentration was 8.2 ppb (inter-quartile range 4.3-18.6 ppb). After 23 years from baseline, 580 participants with prevalent NAFLD (24% prevalence) in midlife were identified. Compared with individuals in the lowest quartile, those in the highest quartile of toenail Cd had a significantly higher odds of NAFLD (OR: 1.43, 95% CI: 1.02, 1.99, P for trend: 0.04) after adjustment for demographics, socioeconomics, major lifestyle factors, and baseline levels of body mass index, lipids, and fasting insulin. The association was not significantly modified by race, sex, BMI, or smoking status at baseline. CONCLUSIONS Toenail Cd concentration was associated with a higher odds of prevalent NAFLD23 years later in life in this cohort of US general population.
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22
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Yang Y, Luan Y, Feng Q, Chen X, Qin B, Ren KD, Luan Y. Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus. Front Pharmacol 2022; 12:807413. [PMID: 35087408 PMCID: PMC8788853 DOI: 10.3389/fphar.2021.807413] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/24/2021] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus is a global public health challenge with high morbidity. Type 2 diabetes mellitus (T2DM) accounts for 90% of the global prevalence of diabetes. T2DM is featured by a combination of defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. However, the pathogenesis of this disease is complicated by genetic and environmental factors, which needs further study. Numerous studies have demonstrated an epigenetic influence on the course of this disease via altering the expression of downstream diabetes-related proteins. Further studies in the field of epigenetics can help to elucidate the mechanisms and identify appropriate treatments. Histone methylation is defined as a common histone mark by adding a methyl group (-CH3) onto a lysine or arginine residue, which can alter the expression of downstream proteins and affect cellular processes. Thus, in tthis study will discuss types and functions of histone methylation and its role in T2DM wilsed. We will review the involvement of histone methyltransferases and histone demethylases in the progression of T2DM and analyze epigenetic-based therapies. We will also discuss the potential application of histone methylation modification as targets for the treatment of T2DM.
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Affiliation(s)
- Yang Yang
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Luan
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Qi Feng
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Xing Chen
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bo Qin
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kai-Di Ren
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Yi Luan
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Cai Q, Gan C, Tang C, Wu H, Gao J. Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease. Front Pharmacol 2021; 12:784591. [PMID: 34887768 PMCID: PMC8650224 DOI: 10.3389/fphar.2021.784591] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/08/2021] [Indexed: 02/05/2023] Open
Abstract
Chronic liver disease (CLD) represents a global health problem, accounting for the heavy burden of disability and increased health care utilization. Epigenome alterations play an important role in the occurrence and progression of CLD. Histone modifications, which include acetylation, methylation, and phosphorylation, represent an essential part of epigenetic modifications that affect the transcriptional activity of genes. Different from genetic mutations, histone modifications are plastic and reversible. They can be modulated pharmacologically without changing the DNA sequence. Thus, there might be chances to establish interventional solutions by targeting histone modifications to reverse CLD. Here we summarized the roles of histone modifications in the context of alcoholic liver disease (ALD), metabolic associated fatty liver disease (MAFLD), viral hepatitis, autoimmune liver disease, drug-induced liver injury (DILI), and liver fibrosis or cirrhosis. The potential targets of histone modifications for translation into therapeutics were also investigated. In prospect, high efficacy and low toxicity drugs that are selectively targeting histone modifications are required to completely reverse CLD and prevent the development of liver cirrhosis and malignancy.
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Affiliation(s)
- Qiuyu Cai
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Can Gan
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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López-Sánchez GN, Dóminguez-Pérez M, Uribe M, Chávez-Tapia NC, Nuño-Lámbarri N. Non-alcoholic fatty liver disease and microRNAs expression, how it affects the development and progression of the disease. Ann Hepatol 2021; 21:100212. [PMID: 32533953 DOI: 10.1016/j.aohep.2020.04.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023]
Abstract
The obesity pandemic that affects the global population generates one of the most unfavorable microenvironmental conditions in the hepatocyte, which triggers the metabolic hepatopathy known as non-alcoholic fatty liver; its annual rates increase in its prevalence and does not seem to improve in the future. The international consortia, LITMUS by the European Union and NIMBLE by the United States of America, have started a race for the development of hepatic steatosis and steatohepatitis reliable biomarkers to have an adequate diagnosis. MicroRNAs have been proposed as diagnostic and prognostic biomarkers involved in adaptation to changes in the liver microenvironment, which could improve clinical intervention strategies in patients with hepatic steatosis.
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Affiliation(s)
- Guillermo Nahúm López-Sánchez
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Mayra Dóminguez-Pérez
- Genomics of Cardiovascular Diseases Laboratory, National Institute of Genomic Medicine, Periferico Sur 4809, Arenal Tepepan, Tlalpan, Z.C. 14610 Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Norberto Carlos Chávez-Tapia
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico; Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico
| | - Natalia Nuño-Lámbarri
- Traslational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Z.C. 14050 Mexico City, Mexico.
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25
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Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD. Int J Mol Sci 2021; 22:ijms222111905. [PMID: 34769333 PMCID: PMC8585051 DOI: 10.3390/ijms222111905] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/30/2021] [Accepted: 10/30/2021] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules' profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging.
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Talens M, Tumas N, Lazarus JV, Benach J, Pericàs JM. What Do We Know about Inequalities in NAFLD Distribution and Outcomes? A Scoping Review. J Clin Med 2021; 10:5019. [PMID: 34768539 PMCID: PMC8584385 DOI: 10.3390/jcm10215019] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/17/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
With prevalence high and rising given the close relationship with obesity and diabetes mellitus, non-alcoholic fatty liver disease (NAFLD) is progressively becoming the most common chronic liver condition worldwide. However, little is known about the health inequalities in NAFLD distribution and outcomes. This review aims to analyze health inequalities in NAFLD distribution globally and to assess the health disparities in NAFLD-related outcomes. We conducted a scoping review of global health inequalities in NAFLD distribution and outcomes according to gender/sex, ethnicity/race, and socioeconomic position from PubMed's inception to May 2021. Ultimately, 20 articles were included in the review, most (75%) of them carried out in the United States. Males were found to have a higher NAFLD prevalence (three articles), while available evidence suggests that women have an overall higher burden of advanced liver disease and complications (four articles), whereas they are less likely to be liver-transplanted once cirrhosis develops (one article). In the US, the Hispanic population had the highest NAFLD prevalence and poorer outcomes (seven articles), whereas Whites had fewer complications than other ethnicities (two articles). Patients with low socioeconomic status had higher NAFLD prevalence (four articles) and a higher likelihood of progression and complications (five articles). In conclusion, globally there is a lack of studies analyzing NAFLD prevalence and outcomes according to various axes of inequality through joint intersectional appraisals, and most studies included in our review were based on the US population. Available evidence suggests that NAFLD distribution and outcomes show large inequalities by social group. Further research on this issue is warranted.
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Affiliation(s)
- Mar Talens
- Research Group on Health Inequalities, Environment, and Employment Conditions, Department of Social and Political Science, Pompeu Fabra University, 08005 Barcelona, Spain; (M.T.); (N.T.); (J.B.)
| | - Natalia Tumas
- Research Group on Health Inequalities, Environment, and Employment Conditions, Department of Social and Political Science, Pompeu Fabra University, 08005 Barcelona, Spain; (M.T.); (N.T.); (J.B.)
- Public Policy Center (UPF-BSM), Johns Hopkins University-Pompeu Fabra University, 08005 Barcelona, Spain
- Centro de Investigaciones y Estudios sobre Cultura y Sociedad, Consejo Nacional de Investigaciones Científicas y Técnicas y Universidad Nacional de Córdoba, Córdoba 5016, Argentina
| | - Jeffrey V. Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain;
| | - Joan Benach
- Research Group on Health Inequalities, Environment, and Employment Conditions, Department of Social and Political Science, Pompeu Fabra University, 08005 Barcelona, Spain; (M.T.); (N.T.); (J.B.)
- Public Policy Center (UPF-BSM), Johns Hopkins University-Pompeu Fabra University, 08005 Barcelona, Spain
- Transdisciplinary Research Group on Socioecological Transitions (GinTrans2), Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Juan M. Pericàs
- Research Group on Health Inequalities, Environment, and Employment Conditions, Department of Social and Political Science, Pompeu Fabra University, 08005 Barcelona, Spain; (M.T.); (N.T.); (J.B.)
- Public Policy Center (UPF-BSM), Johns Hopkins University-Pompeu Fabra University, 08005 Barcelona, Spain
- Liver Unit, Internal Medicine Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute for Research, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
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27
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Zaiou M, Amrani R, Rihn B, Hajri T. Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Biomedicines 2021; 9:1256. [PMID: 34572442 PMCID: PMC8468830 DOI: 10.3390/biomedicines9091256] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to the pathologic buildup of extra fat in the form of triglycerides in liver cells without excessive alcohol intake. NAFLD became the most common cause of chronic liver disease that is tightly associated with key aspects of metabolic disorders, including insulin resistance, obesity, diabetes, and metabolic syndrome. It is generally accepted that multiple mechanisms and pathways are involved in the pathogenesis of NAFLD. Heredity, sedentary lifestyle, westernized high sugar saturated fat diet, metabolic derangements, and gut microbiota, all may interact on a on genetically susceptible individual to cause the disease initiation and progression. While there is an unquestionable role for gene-diet interaction in the etiopathogenesis of NAFLD, it is increasingly apparent that epigenetic processes can orchestrate many aspects of this interaction and provide additional mechanistic insight. Exciting research demonstrated that epigenetic alterations in chromatin can influence gene expression chiefly at the transcriptional level in response to unbalanced diet, and therefore predispose an individual to NAFLD. Thus, further discoveries into molecular epigenetic mechanisms underlying the link between nutrition and aberrant hepatic gene expression can yield new insights into the pathogenesis of NAFLD, and allow innovative epigenetic-based strategies for its early prevention and targeted therapies. Herein, we outline the current knowledge of the interactive role of a high-fat high-calories diet and gene expression through DNA methylation and histone modifications on the pathogenesis of NAFLD. We also provide perspectives on the advancement of the epigenomics in the field and possible shortcomings and limitations ahead.
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Affiliation(s)
- Mohamed Zaiou
- The Jean-Lamour Institute, UMR 7198 CNRS, University of Lorraine, F-54000 Nancy, France;
| | - Rim Amrani
- Department of Neonatology, University Mohammed First, Oujda 60000, Morocco;
| | - Bertrand Rihn
- The Jean-Lamour Institute, UMR 7198 CNRS, University of Lorraine, F-54000 Nancy, France;
| | - Tahar Hajri
- Department of Human Ecology, Delaware State University, Dover, DE 1191, USA;
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Lee J, Song JH, Chung MY, Lee JH, Nam TG, Park JH, Hwang JT, Choi HK. 3,4-dihydroxytoluene, a metabolite of rutin, suppresses the progression of nonalcoholic fatty liver disease in mice by inhibiting p300 histone acetyltransferase activity. Acta Pharmacol Sin 2021; 42:1449-1460. [PMID: 33303988 PMCID: PMC8379200 DOI: 10.1038/s41401-020-00571-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 11/02/2020] [Indexed: 01/07/2023]
Abstract
3,3',4',5,7-Pentahydroxyflavone-3-rhamnoglucoside (rutin) is a flavonoid with a wide range of pharmacological activities. Dietary rutin is hardly absorbed because the microflora in the large intestine metabolize rutin into a variety of compounds including quercetin and phenol derivatives such as 3,4-dihydroxyphenolacetic acid (DHPAA), 3,4-dihydroxytoluene (DHT), 3,4-hydroxyphenylacetic acid (HPAA) and homovanillic acid (HVA). We examined the potential of rutin and its metabolites as novel histone acetyltransferase (HAT) inhibitors. DHPAA, HPAA and DHT at the concentration of 25 μM significantly inhibited in vitro HAT activity with DHT having the strongest inhibitory activity. Furthermore, DHT was shown to be a highly efficient inhibitor of p300 HAT activity, which corresponded with its high degree of inhibition on intracellular lipid accumulation in HepG2 cells. Docking simulation revealed that DHT was bound to the p300 catalytic pocket, bromodomain. Drug affinity responsive target stability (DARTS) analysis further supported the possibility of direct binding between DHT and p300. In HepG2 cells, DHT concentration-dependently abrogated p300-histone binding and induced hypoacetylation of histone subunits H3K9, H3K36, H4K8 and H4K16, eventually leading to the downregulation of lipogenesis-related genes and attenuating lipid accumulation. In ob/ob mice, administration of DHT (10, 20 mg/kg, iv, every other day for 6 weeks) dose-dependently improved the NAFLD pathogenic features including body weight, liver mass, fat mass, lipid accumulation in the liver, and biochemical blood parameters, accompanied by the decreased mRNA expression of lipogenic genes in the liver. Our results demonstrate that DHT, a novel p300 histone acetyltransferase inhibitor, may be a potential preventive or therapeutic agent for NAFLD.
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Dallio M, Romeo M, Gravina AG, Masarone M, Larussa T, Abenavoli L, Persico M, Loguercio C, Federico A. Nutrigenomics and Nutrigenetics in Metabolic- (Dysfunction) Associated Fatty Liver Disease: Novel Insights and Future Perspectives. Nutrients 2021; 13:1679. [PMID: 34063372 PMCID: PMC8156164 DOI: 10.3390/nu13051679] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic- (dysfunction) associated fatty liver disease (MAFLD) represents the predominant hepatopathy and one of the most important systemic, metabolic-related disorders all over the world associated with severe medical and socio-economic repercussions due to its growing prevalence, clinical course (steatohepatitis and/or hepatocellular-carcinoma), and related extra-hepatic comorbidities. To date, no specific medications for the treatment of this condition exist, and the most valid recommendation for patients remains lifestyle change. MAFLD has been associated with metabolic syndrome; its development and progression are widely influenced by the interplay between genetic, environmental, and nutritional factors. Nutrigenetics and nutrigenomics findings suggest nutrition's capability, by acting on the individual genetic background and modifying the specific epigenetic expression as well, to influence patients' clinical outcome. Besides, immunity response is emerging as pivotal in this multifactorial scenario, suggesting the interaction between diet, genetics, and immunity as another tangled network that needs to be explored. The present review describes the genetic background contribution to MAFLD onset and worsening, its possibility to be influenced by nutritional habits, and the interplay between nutrients and immunity as one of the most promising research fields of the future in this context.
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Affiliation(s)
- Marcello Dallio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Mario Romeo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Antonietta Gerarda Gravina
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Mario Masarone
- Department of Medicine and Surgery, University of Salerno, Via Allende, 84081 Baronissi, Italy; (M.M.); (M.P.)
| | - Tiziana Larussa
- Department of Health Sciences, University Magna Graecia, viale Europa, 88100 Catanzaro, Italy; (T.L.); (L.A.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, viale Europa, 88100 Catanzaro, Italy; (T.L.); (L.A.)
| | - Marcello Persico
- Department of Medicine and Surgery, University of Salerno, Via Allende, 84081 Baronissi, Italy; (M.M.); (M.P.)
| | - Carmelina Loguercio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
| | - Alessandro Federico
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy; (M.R.); (A.G.G.); (C.L.); (A.F.)
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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Blázovics A. Alcoholic liver disease. INFLUENCE OF NUTRIENTS, BIOACTIVE COMPOUNDS, AND PLANT EXTRACTS IN LIVER DISEASES 2021:57-82. [DOI: 10.1016/b978-0-12-816488-4.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ramos LF, Silva CM, Pansa CC, Moraes KCM. Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver. Expert Rev Gastroenterol Hepatol 2021; 15:25-40. [PMID: 32892668 DOI: 10.1080/17474124.2020.1820321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed. AREAS COVERED This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized. EXPERT OPINION Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
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Affiliation(s)
- Letícia F Ramos
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Caio M Silva
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Camila C Pansa
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
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The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21238894. [PMID: 33255318 PMCID: PMC7727670 DOI: 10.3390/ijms21238894] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/31/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.
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Yang W, Zhao J, Zhao Y, Li W, Zhao L, Ren Y, Ou R, Xu Y. Hsa_circ_0048179 attenuates free fatty acid-induced steatosis via hsa_circ_0048179/miR-188-3p/GPX4 signaling. Aging (Albany NY) 2020; 12:23996-24008. [PMID: 33221744 PMCID: PMC7762518 DOI: 10.18632/aging.104081] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
Although circular RNAs (circRNAs) are known to play key roles in non-alcoholic fatty liver disease, much about their targets and mechanisms remains unknown. We therefore investigated the actions and mechanisms of hsa_circ_0048179 in an in vitro model of NAFLD. HepG2 cells were exposed to oleate/palmitate (2:1 ratio) for 24 h to induce intracellular lipid accumulation. Using CCK-8 assays, flow cytometry, fluorescence microscopy, western blotting, RT-qPCR, and Oil red O staining, we found that oleate/palmitate treatment reduced cell viability while increasing apoptosis and lipid accumulation in HepG2 cells. Levels of the antioxidant enzyme GPX4 were decreased in oleate/palmitate-treated HepG2 cells, and there were corresponding increases in reactive oxygen species and damage to mitochondrial cristae. Levels of hsa_circ_0048179 expression were also suppressed by oleate/palmitate treatment, and GPX4 levels were markedly increased in HepG2 cells following transfection with hsa_circ_0048179. Analysis of its mechanism revealed that hsa_circ_0048179 upregulated GPX4 levels by acting as a competitive “sponge” of miR-188-3p and that hsa_circ_0048179 attenuated oleate/palmitate-induced lipid accumulation in HepG2 cells by sponging miR-188-3p. Collectively, our findings suggest that hsa_circ_0048179 may play a key role in the pathogenesis of steatosis and may thus be a useful target for drug development.
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Affiliation(s)
- Wenjun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jinduo Zhao
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ye Zhao
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenfeng Li
- Laboratory for Advanced Interdisciplinary Research, Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang Zhao
- Laboratory for Advanced Interdisciplinary Research, Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yi Ren
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32304, USA
| | - Rongying Ou
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Laboratory for Advanced Interdisciplinary Research, Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yunsheng Xu
- Laboratory for Advanced Interdisciplinary Research, Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Dermatovenereology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
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Hyun J, Jung Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020; 21:8138. [PMID: 33143364 PMCID: PMC7662478 DOI: 10.3390/ijms21218138] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 10/28/2020] [Accepted: 10/28/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a widespread hepatic disorder in the United States and other Westernized countries. Nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD, can progress to end-stage liver disease, including cirrhosis and liver cancer. Poor understanding of mechanisms underlying NAFLD progression from simple steatosis to NASH has limited the development of effective therapies and biomarkers. An accumulating body of studies has suggested the importance of DNA methylation, which plays pivotal roles in NAFLD pathogenesis. DNA methylation signatures that can affect gene expression are influenced by environmental and lifestyle experiences such as diet, obesity, and physical activity and are reversible. Hence, DNA methylation signatures and modifiers in NAFLD may provide the basis for developing biomarkers indicating the onset and progression of NAFLD and therapeutics for NAFLD. Herein, we review an update on the recent findings in DNA methylation signatures and their roles in the pathogenesis of NAFLD and broaden people's perspectives on potential DNA methylation-related treatments and biomarkers for NAFLD.
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Affiliation(s)
- Jeongeun Hyun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea
- Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 31116, Korea
- Cell and Matter Institute, Dankook University, Cheonan 31116, Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, Pusan National University, Pusan 46241, Korea
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Combination of luteolin and lycopene effectively protect against the “two-hit” in NAFLD through Sirt1/AMPK signal pathway. Life Sci 2020; 256:117990. [DOI: 10.1016/j.lfs.2020.117990] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023]
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Botello-Manilla AE, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Genetics and epigenetics purpose in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2020; 14:733-748. [PMID: 32552211 DOI: 10.1080/17474124.2020.1780915] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease (NAFLD) comprises a broad spectrum of diseases, which can progress from benign steatosis to nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma. NAFLD is the most common chronic liver disease in developed countries, affecting approximately 25% of the general population. Insulin resistance, adipose tissue dysfunction, mitochondrial and endoplasmic reticulum stress, chronic inflammation, genetic and epigenetic factors are NAFLD triggers that control the disease susceptibility and progression. AREAS COVERED In recent years a large number of investigations have been carried out to elucidate genetic and epigenetic factors in the disease pathogenesis, as well as the search for diagnostic markers and therapeutic targets. This paper objective is to report the most studied genetic and epigenetic variants around NAFLD. EXPERT OPINION NAFLD lead to various comorbidities, which have a considerable impact on the patient wellness and life quality, as well as on the costs they generate for the country's health services. It is essential to continue with molecular research, since it could be used as a clinical tool for prognosis and disease severity. Specifically, in the field of hepatology, plasma miRNAs could provide a novel tool in liver diseases diagnosis and monitoring, representing an alternative to invasive diagnostic procedures.
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Affiliation(s)
| | - Norberto Carlos Chávez-Tapia
- Traslational Research Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico.,Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
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Low Vitamin B12 and Lipid Metabolism: Evidence from Pre-Clinical and Clinical Studies. Nutrients 2020; 12:nu12071925. [PMID: 32610503 PMCID: PMC7400011 DOI: 10.3390/nu12071925] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/19/2020] [Accepted: 06/24/2020] [Indexed: 12/21/2022] Open
Abstract
Obesity is a worldwide epidemic responsible for 5% of global mortality. The risks of developing other key metabolic disorders like diabetes, hypertension and cardiovascular diseases (CVDs) are increased by obesity, causing a great public health concern. A series of epidemiological studies and animal models have demonstrated a relationship between the importance of vitamin B12 (B12) and various components of metabolic syndrome. High prevalence of low B12 levels has been shown in European (27%) and South Indian (32%) patients with type 2 diabetes (T2D). A longitudinal prospective study in pregnant women has shown that low B12 status could independently predict the development of T2D five years after delivery. Likewise, children born to mothers with low B12 levels may have excess fat accumulation which in turn can result in higher insulin resistance and risk of T2D and/or CVD in adulthood. However, the independent role of B12 on lipid metabolism, a key risk factor for cardiometabolic disorders, has not been explored to a larger extent. In this review, we provide evidence from pre-clinical and clinical studies on the role of low B12 status on lipid metabolism and insights on the possible epigenetic mechanisms including DNA methylation, micro-RNA and histone modifications. Although, there are only a few association studies of B12 on epigenetic mechanisms, novel approaches to understand the functional changes caused by these epigenetic markers are warranted.
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Ma P, Huang R, Jiang J, Ding Y, Li T, Ou Y. Potential use of C-phycocyanin in non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2020; 526:906-912. [PMID: 32279997 DOI: 10.1016/j.bbrc.2020.04.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/01/2020] [Indexed: 12/15/2022]
Abstract
C-phycocyanin (C-PC) is a kind of photosynthetically assisted pigment, which is ubiquitous in cyanobacteria cells. We investigated the effect of C-PC on non-alcoholic fatty liver disease (NAFLD) and its mechanism. Through oil red O staining, TC/TG detection, liver SOD/MDA detection and liver H&E staining, we found that C-PC could significantly reduce the lipid accumulation in the steatosis L02 cells and the liver of non-alcoholic steatohepatitis (NASH) mice, and improve the antioxidant capacity of liver. The results of Western Blotting showed that C-PC upregulated the expression of AMPK phosphorylation and downregulated SREBP-1c and its target genes ACC and FAS expression levels. Furthermore, C-PC also upregulated the expression of transcription factor PPARα, which was regulated by AMPK, and its target genes CPT1 level. In addition, C-PC could promote AMPK phosphorylation in hepatocytes while increasing the phosphorylation level of ACC in vivo and in vitro. Besides, C-PC could also improve the liver inflammatory infiltration by upregulated the expression of PPARγ and downregulated the expression of CD36, IL6 and TNFα. These results indicate that C-PC may improve hepatic lipid accumulation and inflammation in the non-alcoholic fatty liver mice by activating AMPK pathway of hepatocytes. The finding provides important help for the research and development of C-PC in the nutraceuticals and therapeutics of NAFLD.
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Affiliation(s)
- Peng Ma
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Rongrong Huang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Jingyao Jiang
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Yuan Ding
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Tingting Li
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China
| | - Yu Ou
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.
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Elbadawy M, Yamanaka M, Goto Y, Hayashi K, Tsunedomi R, Hazama S, Nagano H, Yoshida T, Shibutani M, Ichikawa R, Nakahara J, Omatsu T, Mizutani T, Katayama Y, Shinohara Y, Abugomaa A, Kaneda M, Yamawaki H, Usui T, Sasaki K. Efficacy of primary liver organoid culture from different stages of non-alcoholic steatohepatitis (NASH) mouse model. Biomaterials 2020; 237:119823. [PMID: 32044522 DOI: 10.1016/j.biomaterials.2020.119823] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with liver fibrosis and cirrhosis, which eventually leads to hepatocellular carcinoma. Although several animal models were developed to understand the mechanisms of NASH pathogenesis and progression, it remains obscure. A 3D organoid culture system can recapitulate organ structures and maintain gene expression profiles of original tissues. We therefore tried to generate liver organoids from different degrees [defined as mild (NASH A), moderate (NASH B) and severe (NASH C)] of methionine- and choline-deficient diet-induced NASH model mice and analyzed the difference of their architecture, cell components, organoid-forming efficacy, and gene expression profiles. Organoids from each stage of NASH model mice were successfully generated. Interestingly, epithelial-mesenchymal transition was observed in NASH C organoids. Expression of Collagen I and an activated hepatic stellite cell marker, α-sma was upregulated in the liver organoids from NASH B and C mice. The analysis of RNA sequencing revealed that several novel genes were upregulated in all NASH liver organoids. These results suggest that our generated liver organoids from different stages of NASH diseased mice might become a useful tool for in vitro studies of the molecular mechanism of NASH development and also for identifying novel biomarkers for early diagnosis of NASH disease.
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Affiliation(s)
- Mohamed Elbadawy
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, 13736, Moshtohor, Toukh, Elqaliobiya, Egypt
| | - Megumi Yamanaka
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Goto
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Kimika Hayashi
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan; Department of Translational Research and Developmental Therapeutics Against Cancer, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Ryo Ichikawa
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Junta Nakahara
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tsutomu Omatsu
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tetsuya Mizutani
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yukie Katayama
- Research and Education Center for Prevention of Global Infectious Disease of Animals, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Yuta Shinohara
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan; Pet Health & Food Division, Iskara Industry CO., LTD, 1-14-2, Nihonbashi, Chuo-ku, Tokyo, 103-0027, Japan
| | - Amira Abugomaa
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, 35-1, Higashi 23 Ban-cho, Towada, Aomori, 034-8628, Japan
| | - Tatsuya Usui
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan.
| | - Kazuaki Sasaki
- Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
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Cai Q, Chen F, Xu F, Wang K, Zhang K, Li G, Chen J, Deng H, He Q. Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin α8-mediated activation of RhoA signaling pathway. Metabolism 2020; 104:154140. [PMID: 31926204 DOI: 10.1016/j.metabol.2020.154140] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/04/2019] [Accepted: 01/04/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases that may progress to liver fibrosis or cancer. The present study aimed to investigate the role of microRNA-125b-5p (miR-125b-5p) in NAFLD and to further explore underlying molecular mechanisms. METHODS A mouse model of NAFLD was constructed by high cholesterol diet feeding and a cell-model was developed by treating the mouse liver cell line NCTC1469 with palmitic acid. Gain- and loss-of-function experiments were performed to determine the effects of miR-125b-5p, integrin α8 (ITGA8), and the RhoA signaling pathway on liver fibrosis in NAFLD. After the expression levels of miR-125b-5p, ITGA8, and RhoA were determined, liver fibrosis was evaluated in vivo and in vitro. The binding relationship of miR-125b-5p and ITGA8 was then validated. Finally, miR-125b-5p promoter methylation in NAFLD liver tissues and cells was determined. RESULTS In NAFLD clinical samples, mouse model, and cell-model, miR-125b-5p expression was reduced, while ITGA8 expression was increased. Moreover, miR-125b-5p targeted and downregulated ITGA8, leading to inhibition of the RhoA signaling pathway. In NAFLD liver tissues and cells, the CpG island in the miR-125b-5p promoter was methylated, causing epigenetic silencing of miR-125b-5p. Both miR-125b-5p silencing and ITGA8 overexpression promoted in vitro and in vivo liver fibrosis in NAFLD via activation of the RhoA signaling pathway. CONCLUSIONS Collectively, epigenetic silencing of miR-125b-5p upregulates ITGA8 expression to activate the RhoA signaling pathway, leading to liver fibrosis in NAFLD.
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Affiliation(s)
- Qingxian Cai
- Department of Hepatopathy, The Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, PR China
| | - Fengjuan Chen
- Department of Hepatopathy, Guangzhou Eighth People's Hospital, Guangzhou 510080, PR China
| | - Fen Xu
- Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, GuangdongProvincial Key Laboratory of Diabetology, Guangzhou 510630, PR China
| | - Ke Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
| | - Ka Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China
| | - Guojun Li
- Department of Hepatopathy, The Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, PR China
| | - Jun Chen
- Department of Hepatopathy, The Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, PR China
| | - Hong Deng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, PR China.
| | - Qing He
- Department of Hepatopathy, The Third People's Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, PR China.
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Karaman EF, Zeybel M, Ozden S. Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and α-zearalenol. Toxicol Lett 2020; 326:52-60. [PMID: 32119988 DOI: 10.1016/j.toxlet.2020.02.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/14/2020] [Accepted: 02/27/2020] [Indexed: 01/30/2023]
Abstract
Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of zearalenone and its metabolite alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human hepatocellular carcinoma cells following 24 h of exposure. Zearalenone and alpha zearalenol at the concentrations of 1, 10 and 50 μM significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the chromatin modifying enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 μM of zearalenone exposure using PCR arrays, consistent with the results of global histone modifications. Zearalenone and alpha zearalenol also changed expression levels of the AhR, LXRα, PPARα, PPARɣ, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPARɣ, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPARɣ promoter reduced methylation significantly following zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in zearalenone toxicity. Furthermore, effects of zearalenone in metabolic pathways could be mediated by epigenetic modifications.
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Affiliation(s)
- Ecem Fatma Karaman
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey
| | - Müjdat Zeybel
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, 34010, Topkapi, Istanbul, Turkey
| | - Sibel Ozden
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey.
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Plasticity of histone modifications around Cidea and Cidec genes with secondary bile in the amelioration of developmentally-programmed hepatic steatosis. Sci Rep 2019; 9:17100. [PMID: 31745102 PMCID: PMC6863835 DOI: 10.1038/s41598-019-52943-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022] Open
Abstract
We recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest up-regulation in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (dimethylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes in UN pups only. Changes in these histone modifications may contribute to the markedly down-regulated expression of Cidea and Cidec genes in UN pups, which was observed in the alleviation of hepatic fat deposition, even under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting histone modifications.
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The Level of Vitamin D in Children and Adolescents with Nonalcoholic Fatty Liver Disease: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7643542. [PMID: 31380438 PMCID: PMC6662475 DOI: 10.1155/2019/7643542] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 03/11/2019] [Accepted: 04/28/2019] [Indexed: 02/06/2023]
Abstract
Background The relationship between vitamin D level and NAFLD has not been investigated in children and adolescents. We performed a meta-analysis of published observational studies to assess this association between vitamin D levels (measured as serum 25-hydroxy vitamin D [25(OH)D]) and NAFLD in this age group. Methods Relevant studies conducted before May 20, 2018, were identified from the following electronic databases: PubMed, the Cochrane Library, Embase, and the Chinese CNKI databases. The quality of the included studies was evaluated using the Newcastle Ottawa Scale, and associations between vitamin D levels and NAFLD were estimated using standardised mean differences (SMD) and 95% confidence interval (CI). Subgroup and sensitivity analysis were used to identify sources of heterogeneity, and publication bias was evaluated using funnel plots. Results Eight articles were included in this meta-analysis. A significant difference was observed between low 25(OH)D levels and NAFLD in children and adolescents (SMD = -0.59, 95%CI = -0.98, -0.20, P < 0.01). Subgroup analysis revealed no differences in the study type, geographic location, BMI, and age subgroups. Conclusions Low vitamin D levels were associated with NAFLD in children and adolescents.
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Li Y, Sun JP, Wang J, Lu WH, Xie LY, Lv J, Li HX, Yang SF. Expression of Vsig4 attenuates macrophage-mediated hepatic inflammation and fibrosis in high fat diet (HFD)-induced mice. Biochem Biophys Res Commun 2019; 516:858-865. [PMID: 31266632 DOI: 10.1016/j.bbrc.2019.06.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 06/08/2019] [Indexed: 12/16/2022]
Abstract
The innate immune response contributes to hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). However, the pathogenic mechanism of NAFLD is still poorly understood. The costimulatory molecule V-set and immunoglobulin domain-containing protein-4 (Vsig4), which is exclusively expressed on macrophages, shows significant role in regulating macrophage-mediated inflammation. Here, we attempted to explore if Vsig4 expression was involved in high fat diet (HFD)-induced NAFLD. The results indicated that Vsig4 expression was markedly down-regulated in fatty livers of NAFLD patients and obese mice. Vsig4 knockout accelerated HFD-induced metabolic dysfunction. In addition, the loss of Vsig4 significantly promoted insulin resistance and lipid deposition in liver samples of HFD-challenged mice. Furthermore, HFD-induced inflammation was apparently accelerated in Vsig4 knockout mice by further activating nuclear factor-κB (NF-κB) signaling pathway. Also, Vsig4 deficient mice exhibited greater collagen accumulation in hepatic samples in HFD-challenged mice compared to the WT mice, which was through promoting transforming growth factor-β1 (TGFβ1) signaling. Importantly, we found that lipopolysaccharide (LPS)- or TGFβ1-stimulated inflammation and fibrosis in primary hepatocytes and hepatic stellate cells, respectively, were markedly exacerbated by co-culture with condition medium from bone marrow-derived macrophages (BMDMs) with Vsig4 deficiency. Finally, transplantation of bone marrow cells from control mice to Vsig4-knockout mice restored the severity of steatosis, inflammation and fibrosis after HFD feeding. Therefore, loss of Vsig4 accelerated the severity of lipid deposition, fibrosis and the inflammatory response. Vsig4 could be a therapeutic target for NAFLD treatment.
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Affiliation(s)
- Yang Li
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Ji-Ping Sun
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Jing Wang
- Department of Nephrology, Baoji People's Hospital, Baoji, Shaanxi, 721000, China
| | - Wan-Hong Lu
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, 710061, China
| | - Li-Yi Xie
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, 710061, China
| | - Jing Lv
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, 710061, China
| | - Hui-Xian Li
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, 710061, China
| | - Shi-Feng Yang
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an City, Shaanxi Province, 710061, China.
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Chung S, Hwang JT, Park JH, Choi HK. Free fatty acid-induced histone acetyltransferase activity accelerates lipid accumulation in HepG2 cells. Nutr Res Pract 2019; 13:196-204. [PMID: 31214287 PMCID: PMC6548710 DOI: 10.4162/nrp.2019.13.3.196] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/18/2018] [Accepted: 02/12/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND/OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease triggered by epigenetic alterations, including lysine acetylation at histone or non-histone proteins, affecting the stability or transcription of lipogenic genes. Although various natural dietary compounds have anti-lipogenic effects, their effects on the acetylation status and lipid metabolism in the liver have not been thoroughly investigated. MATERIALS/METHODS Following oleic-palmitic acid (OPA)-induced lipid accumulation in HepG2 cells, the acetylation status of histone and non-histone proteins, HAT activity, and mRNA expression of representative lipogenic genes, including PPARγ, SREBP-1c, ACLY, and FASN, were evaluated. Furthermore, correlations between lipid accumulation and HAT activity for 22 representative natural food extracts (NExs) were evaluated. RESULTS Non-histone protein acetylation increased following OPA treatment and the acetylation of histones H3K9, H4K8, and H4K16 was accelerated, accompanied by an increase in HAT activity. OPA-induced increases in the mRNA expression of lipogenic genes were down-regulated by C-646, a p300/CBP-specific inhibitor. Finally, we detected a positive correlation between HAT activity and lipid accumulation (Pearson's correlation coefficient = 0.604) using 22 NExs. CONCLUSIONS Our results suggest that NExs have novel applications as nutraceutical agents with HAT inhibitor activity for the prevention and treatment of NAFLD.
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Affiliation(s)
- Sangwon Chung
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeonbuk 55365, Republic of Korea
| | - Jin-Taek Hwang
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeonbuk 55365, Republic of Korea.,Department of Food Biotechnology, Korea University of Science & Technology, Daejeon 34113, Republic of Korea
| | - Jae Ho Park
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeonbuk 55365, Republic of Korea
| | - Hyo-Kyoung Choi
- Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeonbuk 55365, Republic of Korea
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Asprouli E, Kalafati IP, Sakellari A, Karavoltsos S, Vlachogiannakos J, Revenas K, Kokkinos A, Dassenakis M, Dedoussis GV, Kalogeropoulos N. Evaluation of Plasma Trace Elements in Different Stages of Nonalcoholic Fatty Liver Disease. Biol Trace Elem Res 2019; 188:326-333. [PMID: 30014284 DOI: 10.1007/s12011-018-1432-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/03/2018] [Indexed: 01/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. Its global prevalence is estimated between 25 and 45%, occurring mainly in overweight individuals with unhealthy dietary habits and low levels of physical activity. Many studies have investigated the association of trace elements with liver diseases, though not with NAFLD. In this work, we investigated trace element levels in plasma of patients and not-patients and their possible association with various stages of the disease. Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the determination of As, Ba, Cd, Co, Cs, Cu, Fe, Rb, Sr, Tl, and Zn in the plasma of 189 free-living residents of Athens, Greece, either healthy or patients with mild, moderate, or severe NAFLD. The disease was diagnosed by abdominal ultrasound; blood samples were analyzed for total, HDL and LDL cholesterol, triglycerides, fasting glucose, fasting insulin, and liver enzymes, namely aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyltransferase (Gamma-GT); insulin resistance was determined by the homeostatic model assessment (HOMA-IR). Zinc exhibited a statistically significant negative association with the severity of the disease, while cesium showed a statistically significant positive association. Moreover, thallium and iron were inversely associated with insulin levels. Trace element determination in plasma could be useful for establishing relationships with NAFLD status of patients. Further research is required for the verification and interpretation of these findings.
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Affiliation(s)
- Eleni Asprouli
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece
- Laboratory of Environmental Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece
| | - Aikaterini Sakellari
- Laboratory of Environmental Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - Sotirios Karavoltsos
- Laboratory of Environmental Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - John Vlachogiannakos
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Revenas
- Radiology Department, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic and Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Manos Dassenakis
- Laboratory of Environmental Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
| | - George V Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece
| | - Nick Kalogeropoulos
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece.
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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases. Nutr Res Rev 2019; 32:128-145. [PMID: 30707092 DOI: 10.1017/s0954422418000239] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
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Gerosa C, Fanni D, Congiu T, Piras M, Cau F, Moi M, Faa G. Liver pathology in Wilson's disease: From copper overload to cirrhosis. J Inorg Biochem 2019; 193:106-111. [PMID: 30703747 DOI: 10.1016/j.jinorgbio.2019.01.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/11/2019] [Accepted: 01/12/2019] [Indexed: 02/07/2023]
Abstract
Wilson's disease (WD) is a genetic metabolic disease strictly associated with liver cirrhosis. In this review, the genetic bases of the disease are discussed, with emphasis on the role of ATP7B (the Wilson disease protein) dysfunction as a determinant factor of systemic copper overload. Regarding the different multiple mutations described in WD patients, the peculiarity of Sardinian population is highlighted, Sardinians carrying a rare deletion in the promoter (5' UTR) of the WD gene. The role of epigenetic changes in the clinical presentation and evolution of liver disease in WD patients is also discussed, nutrition probably representing a relevantly risk factor in WD patients. The role of transmission electron microscopy in the diagnosis of WD-related liver disease is underlined. Mitochondrial changes, increased peroxisomes fat droplets, lipolysosomes and intranuclear glycogen inclusions are reported as the most frequent ultrastructural changes in the liver of WD carriers. The role of histochemical stains for copper is analyzed, and the Timm's method is suggested as the most sensitive one for revealing hepatic copper overload in all stage of WD. The marked variability of the histological liver changes occurring in WD is underlined simple steatosis may represent the only pathological changes, frequently associated with glycogenated nuclei. Mallory-Denk bodies lipogranulomas alcoholic and non-alcoholic fatty liver disease ending with bridging fibrosis and cirrhosis. Finally, the reversal of fibrosis as a possible therapeutic objective in WD is discussed.
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Affiliation(s)
- C Gerosa
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - D Fanni
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - T Congiu
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - M Piras
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy.
| | - F Cau
- Division of Pathological, San Gavino Hospital, ATS, San Gavino, Italy
| | - M Moi
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
| | - G Faa
- Division of Pathological, University of Cagliari AOU Cagliari, Cagliari, Italy
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Abstract
Purpose of review Advancing our understanding of the mechanisms that underlie NASH pathogenesis. Recent findings Recent findings on NASH pathogenesis have expanded our understanding of its complexity including: (1) there are multiple parallel hits that lead to NASH; (2) the microbiota play an important role in pathogenesis, with bacterial species recently shown to accurately differentiate between NAFL and NASH patients; (3) the main drivers of liver cell injury are lipotoxicity caused by free fatty acids (FFAs) and their derivatives combined with mitochondrial dysfunction; (4) decreased endoplasmic reticulum (ER) efficiency with increased demand for protein synthesis/folding/repair results in ER stress, protracted unfolded protein response, and apoptosis; (5) upregulated proteins involved in multiple pathways including JNK, CHOP, PERK, BH3-only proteins, and caspases result in mitochondrial dysfunction and apoptosis; and (6) subtypes of NASH in which these pathophysiological pathways vary may require patient subtype identification to choose effective therapy. Summary Recent pathogenesis studies may lead to important therapeutic advances, already seen in patients treated with ACC, ASK1 and SCD1 inhibitors and FXR agonists. Further advancing our understanding of mechanisms underlying NASH pathogenesis and the complex interplay between them will be crucial for developing effective therapies.
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