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1
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Park KY, Hong S, Kim KS, Han K, Park CY. Prolonged Use of Carnitine-Orotate Complex (Godex ®) Is Associated with Improved Mortality: A Nationwide Cohort Study. J Pers Med 2022; 12:jpm12121970. [PMID: 36556191 PMCID: PMC9787718 DOI: 10.3390/jpm12121970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 11/24/2022] [Indexed: 11/30/2022] Open
Abstract
Despite its hepatoprotective effects and favorable metabolic effects, the association between carnitine-orotate complex (Godex®) intake and mortality has never been investigated. We enrolled 13,413 adults who underwent national health examination and were prescribed the carnitine-orotate complex. Subjects were classified into three groups based on duration of using carnitine-orotate complex: <30, 30−180, and ≥180 days and were followed-up until 2019. Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality were estimated using Cox proportional hazards regression. During the follow-up period, 708 deaths were documented. Adjusted HR of mortality was 0.69 (95% CI 0.51−0.92) in those who used carnitine-orotate complex for ≥180 days compared to those who used it for <30 days. Use of carnitine-orotate complex for ≥180 days was associated with significantly reduced mortality in individuals with metabolic risk factors such as obesity, metabolic syndrome, dyslipidemia, and fatty liver than the shorter period of use. A significant interaction was observed in individuals with type 2 diabetes (HR 0.43, 95% CI 0.29−0.63, p-value 0.001). In this nationwide study, longer use of carnitine-orotate complex was associated with improved mortality compared to a shorter period of use, and the risk reductions were prominent in individuals with metabolic risk factors.
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Affiliation(s)
- Kye-Yeung Park
- Department of Family Medicine, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
| | - Sangmo Hong
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Republic of Korea
| | - Kyung-Soo Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13497, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul 06978, Republic of Korea
| | - Cheol-Young Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
- Correspondence: ; Tel.: +82-2-2001-1869; Fax: +82-2001-1588
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Shu Z, Zhang G, Zhu X, Xiong W. Estrogen receptor α mediated M1/M2 macrophages polarization plays a critical role in NASH of female mice. Biochem Biophys Res Commun 2022; 596:63-70. [PMID: 35114586 DOI: 10.1016/j.bbrc.2022.01.085] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/23/2022] [Indexed: 12/11/2022]
Abstract
Owing to lacking protective effect of estrogen, OVX mice have higher risk of non-alcoholic fatty liver disease compared with normal female mice, when fed with high fat diet. Our study was to explore how estrogen protect against nonalcoholic steatohepatitis in female mice. We found that, lacking estrogen, M1 macrphages was activated and promoted steatohepatitis in obese OVX mice. And, ERα was responsible for estrogen to inhibit M1 macrphages activation and steatohepatitis. ERα knockdown aggravated M1 macrophages infiltration by transcriptionally upregulated its CCR2 expression. CCR2 antagonist effectively improved nonalcoholic steatohepatitis, ER stress and insulin resistance in ERα knockdown obese female mice. These results demonstrated ERα mediated M1 macrophages activation played a key role in nonalcoholic steatohepatitis.
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Affiliation(s)
- Zhiping Shu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China
| | - Guopeng Zhang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China
| | - Xiaohua Zhu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China.
| | - Wenqian Xiong
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 JieFang Avenue, Wuhan, 430030, China.
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3
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Sun X, Zhu S, Dong X, Strand-Amundsen RJ, Tonnessen TI, Yang R. Ethyl pyruvate supplemented in drinking water ameliorates experimental nonalcoholic steatohepatitis. Biomed Pharmacother 2021; 137:111392. [PMID: 33761609 DOI: 10.1016/j.biopha.2021.111392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/22/2021] [Accepted: 02/10/2021] [Indexed: 02/09/2023] Open
Abstract
Inflammation and oxidative stress play a significant role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Ethyl pyruvate (EP) is a novel anti-inflammatory agent and a potent reactive oxygen species (ROS) scavenger. Therefore, EP supplemented in drinking water may alleviate experimental NASH in this study (even though 0.3% of EP cannot attenuate the simple non-aggressive fatty liver). The methionine-choline-deficient (MCD) diet was given to the C57BL/6 male mice for 3 weeks to induce NASH. The NASH animals were randomized into 3 treatment groups: animals in the MCD alone group were treated with normal drinking water alone; animals in the delayed EP group were given 3% (v/v) of EP supplemented in normal drinking water, the treatment started 10 days after MCD diet feeding; animals in the early EP therapy group were treated the same as the delayed EP group except that EP treatment started the same day when MCD diet was given; the control mice were fed with normal chow and treated with normal drinking water (n = 10 for each group). Compared to MCD group with normal drinking water, early EP treatment significantly decreased serum ALT and improved NASH histopathology; delayed EP therapy only attenuated NASH in 50% (5/10) of the animals. The beneficial effects were associated with decreased hepatic TNF-a and IL-6 mRNA expression on early 5 days, inhibited NF-kB activation, reduced liver tissue malondialdehyde levels, and decreased intestinal bacterial translocation (BT). In conclusion: EP supplemented in drinking water attenuates experimental NASH.
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Affiliation(s)
- Xiujing Sun
- Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shengtao Zhu
- Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xueyu Dong
- Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Runar J Strand-Amundsen
- Department of Clinical and Biomedical Engineering, Oslo University Hospital, 4950 Nydalen, 0424 Oslo, Norway
| | - Tor Inge Tonnessen
- Department of Emergencies and Critical Care, Oslo University Hospital, 4950 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, 0316 Blindern, Oslo, Norway
| | - Runkuan Yang
- Department of Emergencies and Critical Care, Oslo University Hospital, 4950 Nydalen, 0424 Oslo, Norway.
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Forni C, Facchiano F, Bartoli M, Pieretti S, Facchiano A, D'Arcangelo D, Norelli S, Valle G, Nisini R, Beninati S, Tabolacci C, Jadeja RN. Beneficial Role of Phytochemicals on Oxidative Stress and Age-Related Diseases. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8748253. [PMID: 31080832 PMCID: PMC6475554 DOI: 10.1155/2019/8748253] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/11/2019] [Accepted: 03/20/2019] [Indexed: 12/17/2022]
Abstract
Aging is related to a number of functional and morphological changes leading to progressive decline of the biological functions of an organism. Reactive Oxygen Species (ROS), released by several endogenous and exogenous processes, may cause important oxidative damage to DNA, proteins, and lipids, leading to important cellular dysfunctions. The imbalance between ROS production and antioxidant defenses brings to oxidative stress conditions and, related to accumulation of ROS, aging-associated diseases. The purpose of this review is to provide an overview of the most relevant data reported in literature on the natural compounds, mainly phytochemicals, with antioxidant activity and their potential protective effects on age-related diseases such as metabolic syndrome, diabetes, cardiovascular disease, cancer, neurodegenerative disease, and chronic inflammation, and possibly lower side effects, when compared to other drugs.
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Affiliation(s)
- Cinzia Forni
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Francesco Facchiano
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Manuela Bartoli
- Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Stefano Pieretti
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Antonio Facchiano
- Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy
| | - Daniela D'Arcangelo
- Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy
| | - Sandro Norelli
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Giorgia Valle
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Nisini
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Simone Beninati
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | | | - Ravirajsinh N. Jadeja
- Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA, USA
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Haidara MA, Dallak M, El Karib AO, Abd Ellatif M, Eid RA, Heidar EHA, Al-Ani B. Insulin protects against hepatocyte ultrastructural damage induced by type 1 diabetes mellitus in rats. Ultrastruct Pathol 2018; 42:508-515. [PMID: 30497321 DOI: 10.1080/01913123.2018.1551258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 11/19/2018] [Indexed: 02/08/2023]
Abstract
Diabetic complications that affect vital organs such as the heart and liver represent a major public health concern. The potential protective effects of the hormone insulin against hepatocyte ultrastructural alterations induced secondary to type 1 diabetes mellitus (T1DM) in a rat model of the disease have not been investigated before. Therefore, rats were injected once with 65 mg/kg streptozotocin (T1DM group) and the protection group (T1DM+Ins) received a daily injection of insulin 48 h post diabetic induction by streptozotocin and continued until being sacrificed at week 8. The harvested liver tissues were examined using transmission electron microscopy (TEM) and blood samples were assayed for biomarkers of liver injury enzyme, glycemia, lipidemia, inflammation, and oxidative stress. TEM images showed that T1DM induced profound hepatocyte ultrastructural alterations as demonstrated by pyknotic nucleus, condensation of chromatin, irregular nuclear membrane, swollen mitochondria, dilated rough endoplasmic reticulum, damaged intercellular space, and accumulation of few lipid droplets inside the hepatocyte cytoplasm, which were substantially protected with insulin. In addition, the blood chemistry profile complements the TEM data as demonstrated by an increase in serum levels of alanine aminotransferase (ALT), dyslipidemia, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA) by T1DM that were significantly (p < 0.05) reduced with insulin injections. Thus, we conclude that insulin effectively protects against T1DM-induced liver injury in rats for a period of 8 weeks, possibly due to the inhibition of inflammation, oxidative stress, and dyslipidemia.
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Affiliation(s)
- Mohamed A Haidara
- a Departments of Physiology , College of Medicine, King Khalid University , Abha , Saudi Arabia
- b Physiology Department, Kasr al-Aini Faculty of Medicine , Cairo University , Cairo , Egypt
| | - Mohammad Dallak
- a Departments of Physiology , College of Medicine, King Khalid University , Abha , Saudi Arabia
| | - Abbas O El Karib
- a Departments of Physiology , College of Medicine, King Khalid University , Abha , Saudi Arabia
| | - Mohamed Abd Ellatif
- c Clinical Biochemistry , College of Medicine, King Khalid University , Abha , Saudi Arabia
- d Department of Medical Biochemistry, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Refaat A Eid
- e Pathology Department , College of Medicine, King Khalid University , Abha , Saudi Arabia
| | - El Hassan A Heidar
- f Anatomy Department , College of Medicine, King Khalid University , Abha , Saudi Arabia
- g Department of Anatomy , kasr al-Aini Faculty of Medicine, Cairo University , Cairo , Egypt
| | - Bahjat Al-Ani
- a Departments of Physiology , College of Medicine, King Khalid University , Abha , Saudi Arabia
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Catalase and nonalcoholic fatty liver disease. Pflugers Arch 2018; 470:1721-1737. [PMID: 30120555 DOI: 10.1007/s00424-018-2195-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/01/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023]
Abstract
Obesity and insulin resistance are considered the main causes of nonalcoholic fatty liver disease (NAFLD), and oxidative stress accelerates the progression of NAFLD. Free fatty acids, which are elevated in the liver by obesity or insulin resistance, lead to incomplete oxidation in the mitochondria, peroxisomes, and microsomes, leading to the production of reactive oxygen species (ROS). Among the ROS generated, H2O2 is mainly produced in peroxisomes and decomposed by catalase. However, when the H2O2 concentration increases because of decreased expression or activity of catalase, it migrates to cytosol and other organelles, causing cell injury and participating in the Fenton reaction, resulting in serious oxidative stress. To date, numerous studies have been shown to inhibit the pathogenesis of NAFLD, but treatment for this disease mainly depends on weight loss and exercise. Various molecules such as vitamin E, metformin, liraglutide, and resveratrol have been proposed as therapeutic agents, but further verification of the dose setting, clinical application, and side effects is needed. Reducing oxidative stress may be a fundamental method for improving not only the progression of NAFLD but also obesity and insulin resistance. However, the relationship between NAFLD progression and antioxidants, particularly catalase, which is most commonly expressed in the liver, remains unclear. Therefore, this review summarizes the role of catalase, focusing on its potential therapeutic effects in NAFLD progression.
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Borrelli A, Bonelli P, Tuccillo FM, Goldfine ID, Evans JL, Buonaguro FM, Mancini A. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches. Redox Biol 2018; 15:467-479. [PMID: 29413959 PMCID: PMC5975181 DOI: 10.1016/j.redox.2018.01.009] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 01/10/2018] [Accepted: 01/17/2018] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.
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Affiliation(s)
- Antonella Borrelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy.
| | - Patrizia Bonelli
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Franca Maria Tuccillo
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | | | | | - Franco Maria Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G Pascale", 80131 Napoli, Italy
| | - Aldo Mancini
- Leadhexa Biotechnologies Inc., Belvedere, CA, USA
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Kim HM, Kim Y, Lee ES, Huh JH, Chung CH. Caffeic acid ameliorates hepatic steatosis and reduces ER stress in high fat diet-induced obese mice by regulating autophagy. Nutrition 2018; 55-56:63-70. [PMID: 29960159 DOI: 10.1016/j.nut.2018.03.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 03/07/2018] [Accepted: 03/10/2018] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Non-alcoholic fatty liver disease is characterized by high hepatic triacylglycerol contents, which is associated with endoplasmic reticulum (ER) stress and insulin resistance. Caffeic acid (CA) has antioxidant, immunomodulatory, and antiinflammatory effects. We investigated the effects of CA on hepatic steatosis and its mechanism of action. METHODS We treated CA (50 µM) with AML12 cells. We categorized mice into three groups as follows: low-fat diet mice (LFD, n = 10), high-fat diet-induced obese mice (HFD, n = 10), and HFD fed with CA (50 mg/kg/d, n = 10) for 10 wk. RESULTS CA did not cause any cytotoxic effect on AML12 cell line within the range of concentrations tested (0-200 µM). We found that CA (50 µM) treatment in palmitate-treated AML12 hepatocytes reduced lipid accumulation and lipogenesis markers, decreased ER stress, and increased autophagy markers. However, there was no significant difference in lipid droplets of palmitate-treated AML12 hepatocytes and CA-treated autophagy-related protein 7 deficiency AML12 hepatocytes with palmitate. Similarly, CA significantly lowered body and liver weights. Lipid accumulation in the liver decreased in the HFD + CA group compared with the HFD group. Glucose intolerance and insulin sensitivity also were markedly improved in the HFD + CA group. Moreover, the levels of ER stress markers were decreased in the livers of the HFD + CA group. CONCLUSION Autophagy markers were increased in the livers of the HFD + CA group. These results suggest that caffeic acid may ameliorate hepatic steatosis and decrease ER stress by increasing autophagy.
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Affiliation(s)
- Hong Min Kim
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Yuna Kim
- Department of Endocrinology and Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Eun Soo Lee
- Department of Endocrinology and Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Ji Hye Huh
- Department of Endocrinology and Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Choon Hee Chung
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Department of Endocrinology and Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
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Lin S, Xian Y, Liu Y, Cai W, Song J, Zhang X. Risk factors and community intervention for nonalcoholic fatty liver disease in community residents of Urumqi, China. Medicine (Baltimore) 2018; 97:e0021. [PMID: 29489647 PMCID: PMC5851716 DOI: 10.1097/md.0000000000010021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
This study is to investigate the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) and to analyze the effect of comprehensive community intervention on NAFLD in community residents in Urumqi, China.Cluster sampling method with street community as a unit was adopted in this study. Questionnaire survey, body measurement, blood biochemistry (including liver function, fasting blood glucose [FPG], and uric acid [UA]) examination as well as liver B ultrasound were performed. Then, comprehensive intervention was conducted in NAFLD patients.A total of 1000 people were enrolled, including 344 men and 656 women, with an average age of 51.79 ± 4.28 years. Of them, 660 were Han Chinese, 327 were Uygur, and 13 were Hui. The overall prevalence rate of NAFLD was 54.3%. The prevalence rate of NAFLD is higher in middle-aged population and is higher in ethnic minority than that in Han. NAFLD was associated with the past medical history of metabolic diseases. The factors of body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, hip circumference, neck circumference, subcutaneous fat thickness, FPG, alanine aminotransferase, and aspartate aminotransferase were identified as risk factors for NFALD. Neck circumference predicts the occurrence of NAFLD in female better, whereas subcutaneous fat predicts the occurrence of NAFLD in male better. After 8 months of community intervention in NAFLD patients, the changes of BMI, SBP, DBP, waist circumference, neck circumference, subcutaneous fat thickness, and UA were statistically significant (P < .05).The prevalence rate of NAFLD is high in Urumqi, China. Community intervention is effective in reducing the degree of NAFLD and promoting the overall health of NAFLD patients.
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Affiliation(s)
- Sulan Lin
- Department of Clinical Teaching and Research, School of Nursing, Xinjiang Medical University
| | - Yajing Xian
- Department of Clinical Teaching and Research, School of Nursing, Xinjiang Medical University
| | - Yi Liu
- Outpatient Clinic, Urumqi Traditional Chinese Medicine Hospital
| | - Wen Cai
- Department of Clinical Teaching and Research, School of Nursing, Xinjiang Medical University
| | - Jiangmei Song
- Department of Infectious Diseases, the First Affiliated Hospital of Xinjiang Medical University
| | - Xiangyang Zhang
- Department of Health Management, School of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, China
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10
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Wang S, Li X, Guo H, Yuan Z, Wang T, Zhang L, Jiang Z. Emodin alleviates hepatic steatosis by inhibiting sterol regulatory element binding protein 1 activity by way of the calcium/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mechanistic target of rapamycin-p70 ribosomal S6 kinase signaling pathway. Hepatol Res 2017; 47:683-701. [PMID: 27492505 DOI: 10.1111/hepr.12788] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 07/21/2016] [Accepted: 08/01/2016] [Indexed: 12/14/2022]
Abstract
AIM To investigate the effects of emodin on the treatment of non-alcoholic fatty liver and the underlying mechanisms. METHODS In vitro, hepatocytes were treated with 1 mM free fatty acid together with various concentrations of emodin. In vivo, Sprague-Dawley rats were divided into a control group, high-fat diet (HFD) group, and three HFD groups treated with 40, 80, and 160 mg/kg emodin, respectively. After being fed a HFD for 4 weeks, rats were orally dosed with emodin once daily for 8 weeks. The biochemical parameters and histology features were examined. The expression of lipogenic and lipolytic gene and protein and the phosphorylation of calcium/calmodulin-dependent kinase kinase (CaMKK), AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6K) were measured in vitro and in vivo. RESULTS Emodin improved lipid accumulation in vitro and in vivo. Emodin downregulated the levels of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes but increased lipolysis-related proteins and mRNA. Phosphorylation of AMPK was increased, while phosphorylation of mTOR and p70S6K were suppressed by emodin. The nuclear translocation of SREBP1 was inhibited by emodin by AMPK and mTOR. Emodin activated AMPK by CaMKK and reversed the reduction of CaMKK in HFD-fed rats. CONCLUSION Emodin effectively ameliorates hepatic steatosis through the CaMKK-AMPK-mTOR-p70S6K-SREBP1 signaling pathway.
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Affiliation(s)
- Shaojie Wang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xiaojie Li
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Hongli Guo
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Zihang Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Tao Wang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.,Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, China Pharmaceutical University, Nanjing, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.,Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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11
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Bilal HM, Riaz F, Munir K, Saqib A, Sarwar MR. Histological changes in the liver of diabetic rats: A review of pathogenesis of nonalcoholic fatty liver disease in type 1 diabetes mellitus. COGENT MEDICINE 2017. [DOI: 10.1080/2331205x.2016.1275415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
| | - Fatima Riaz
- Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Kiran Munir
- Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Anum Saqib
- Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Muhammad Rehan Sarwar
- Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
- Akhtar Saeed College of Pharmaceutical Sciences, Lahore, Pakistan
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12
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Vecchione G, Grasselli E, Voci A, Baldini F, Grattagliano I, Wang DQH, Portincasa P, Vergani L. Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. World J Gastroenterol 2016; 22:6016-6026. [PMID: 27468193 PMCID: PMC4948277 DOI: 10.3748/wjg.v22.i26.6016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/19/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis. METHODS Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays. RESULTS Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation. CONCLUSION We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.
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Di Minno MND, Di Minno A, Ambrosino P, Songia P, Tremoli E, Poggio P. Aortic valve sclerosis as a marker of atherosclerosis: Novel insights from hepatic steatosis. Int J Cardiol 2016; 217:1-6. [PMID: 27164417 DOI: 10.1016/j.ijcard.2016.04.162] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/29/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nowadays, aortic valve sclerosis (AVSc) might be considered an atherosclerosis-like process due to significant association with age, male gender and some major features of metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) has been recognized as a clinical expression of the metabolic syndrome and as a predictor of cardiovascular events. We aim, with this meta-analysis, to evaluate the correlation between NAFLD and AVSc; this finding might suggest new insights and interactions among NAFLD, AVSc and the atherosclerotic process. METHODS AND RESULTS A detailed search was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to identify all studies providing data about the association between AVSc and NAFLD. 3 studies enrolling a total of 1172 patients with NAFLD and 1467 controls without NAFLD were included in the meta-analysis. The prevalence of AVSc was 41.3% (95% CI: 32.0%, 51.4%) in NAFLD patients and 24.6% (18.4%, 32.0%) in subjects without NAFLD with a corresponding OR of 2.28 (95% CI: 1.21, 4.28, p=0.01, I(2): 77.6%, p=0.011). A meta-regression analysis showed that age, prevalence of male gender, hypertension, body mass index, and dyslipidemia were directly and significantly associated with the difference in the prevalence of AVSc between patients with NAFLD and those without. CONCLUSIONS In conclusion, our meta-analysis shows a significant association between NAFLD and AVSc. However, further evidence is needed to validate these findings and find out if there is a real link or just a mere association.
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Affiliation(s)
- Matteo Nicola Dario Di Minno
- Centro Cardiologico Monzino, IRCCS, Milan, Italy; Department of Advanced Biomedical Sciences, Division of Cardiology, Federico II University, Naples, Italy
| | - Alessandro Di Minno
- Centro Cardiologico Monzino, IRCCS, Milan, Italy; University of Milan, Department of Pharmacological and Biomolecular Sciences, Milan, Italy
| | - Pasquale Ambrosino
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Paola Songia
- Centro Cardiologico Monzino, IRCCS, Milan, Italy; University of Milan, Department of Pharmacological and Biomolecular Sciences, Milan, Italy
| | | | - Paolo Poggio
- Centro Cardiologico Monzino, IRCCS, Milan, Italy.
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14
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Lee SH, Kim KN, Kim KM, Joo NS. Irritable Bowel Syndrome May Be Associated with Elevated Alanine Aminotransferase and Metabolic Syndrome. Yonsei Med J 2016; 57:146-52. [PMID: 26632395 PMCID: PMC4696946 DOI: 10.3349/ymj.2016.57.1.146] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 02/13/2015] [Accepted: 02/27/2015] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Recent studies have revealed close relationships between hepatic injury, metabolic pathways, and gut microbiota. The microorganisms in the intestine also cause irritable bowel syndrome (IBS). The aim of this study was to examine whether IBS was associated with elevated hepatic enzyme [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], gamma-glutamyl transferase (γ-GT) levels, and metabolic syndrome (MS). MATERIALS AND METHODS This was a retrospective, cross-sectional, case-control study. The case and control groups comprised subjects who visited our health promotion center for general check-ups from June 2010 to December 2010. Of the 1127 initially screened subjects, 83 had IBS according to the Rome III criteria. The control group consisted of 260 age- and sex-matched subjects without IBS who visited our health promotion center during the same period. RESULTS Compared to control subjects, patients with IBS showed significantly higher values of anthropometric parameters (body mass index, waist circumference), liver enzymes, γ-GT, and lipid levels. The prevalences of elevated ALT (16.9% vs. 7.7%; p=0.015) and γ-GT (24.1% vs. 11.5%; p=0.037) levels were significantly higher in patients with IBS than in control subjects. A statistically significant difference was observed in the prevalence of MS between controls and IBS patients (12.7% vs. 32.5%; p<0.001). The relationships between elevated ALT levels, MS, and IBS remained statistically significant after controlling for potential confounding factors. CONCLUSION On the basis of our study results, IBS may be an important condition in certain patients with elevated ALT levels and MS.
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Affiliation(s)
- Seung Hwa Lee
- Department of Family Medicine, Seo-Hae Hospital, Seocheon, Korea
| | - Kyu Nam Kim
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea.
| | - Kwang Min Kim
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
| | - Nam Seok Joo
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
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15
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Asrih M, Altirriba J, Rohner-Jeanrenaud F, Jornayvaz FR. Ketogenic Diet Impairs FGF21 Signaling and Promotes Differential Inflammatory Responses in the Liver and White Adipose Tissue. PLoS One 2015; 10:e0126364. [PMID: 25973847 PMCID: PMC4431718 DOI: 10.1371/journal.pone.0126364] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 04/01/2015] [Indexed: 12/25/2022] Open
Abstract
Background/Hypothesis Beside its beneficial effects on weight loss, ketogenic diet (KD) causes dyslipidemia, a pro-inflammatory state involved in the development of hepatic steatosis, glucose intolerance and insulin resistance, although the latter is still being debated. Additionally, KD is known to increase fibroblast growth factor 21 (FGF21) plasma levels. However, FGF21 cannot initiate its beneficial actions on metabolism in these conditions. We therefore hypothesized and tested in the present study that KD may impair FGF21 signaling. Methods/Results Using indirect calorimetry, we found that KD-fed mice exhibited higher energy expenditure than regular chow (RC)-fed mice associated with increased Ucp1 levels in white adipose tissue (WAT), along with increased plasma FGF21 levels. We then assessed the effect of KD on FGF21 signaling in both the liver and WAT. We found that Fgfr4 and Klb (β-klotho) were downregulated in the liver, while Fgfr1 was downregulated in WAT of KD-fed mice. Because inflammation could be one of the mechanisms linking KD to impaired FGF21 signaling, we measured the expression levels of inflammatory markers and macrophage accumulation in WAT and liver and found an increased inflammation and macrophage accumulation in the liver, but surprisingly, a reduction of inflammation in WAT.We also showed that KD enhances lipid accumulation in the liver, which may explain hepatic inflammation and impaired Fgfr4 and Klb expression. In contrast, import of lipids from the circulation was significantly reduced in WAT of KD-fed mice, as suggested by a downregulation of Lpl and Cd36. This was further associated with reduced inflammation in WAT. Conclusion Altogether, these results indicate that KD could be beneficial for a given tissue but deleterious for another.
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Affiliation(s)
- Mohamed Asrih
- Division of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
| | - Jordi Altirriba
- Division of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
| | - Françoise Rohner-Jeanrenaud
- Division of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
| | - François R. Jornayvaz
- Division of Endocrinology, Diabetes, Hypertension and Nutrition, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
- * E-mail:
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16
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Borges Haubert NJBG, Marchini JS, Carvalho Cunha SF, Suen VMM, Padovan GJ, Jordao AA, Marchini Alves CMM, Marchini JFM, Vannucchi H. Choline and Fructooligosaccharide: Non-alcoholic Fatty Liver Disease, Cardiac Fat Deposition, and Oxidative Stress Markers. Nutr Metab Insights 2015; 8:1-6. [PMID: 25987847 PMCID: PMC4425195 DOI: 10.4137/nmi.s24385] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 03/01/2015] [Accepted: 03/03/2015] [Indexed: 12/17/2022] Open
Abstract
This study investigates the treatment of non-alcoholic fatty liver disease (NAFLD) in rats with choline and fructooligosaccharide (FOS). The healthy control group received standard diet. The other three groups consisted of animals with NAFLD. Group Estr received standard diet; group Echo received standard diet plus choline (3 g/100 g diet); and group Efos received standard diet plus FOS (10 g/100 g diet). Food intake, weight, urinary nitrogen, urinary ammonia, total cholesterol, serum triacylglyceride, liver and heart weights, tissue nitrogen, tissue fat, vitamin E, TBARS, and reduced glutathione (GSH) were measured in hepatic and heart tissue. Choline and FOS treatments resulted in total mean fat reduction in liver and heart tissue of 0.2 and 1.7 g, respectively. Both treatments were equally effective in reducing hepatic and cardiac steatosis. There were no differences in the TBARS level among experimental and control groups, indicating that the proposed treatments had no added protection against free radicals. While all experimental groups had increased vitamin E and GSH levels, choline treatment led to a significant increase compared to control.
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Affiliation(s)
| | | | | | | | | | - Alceu Afonso Jordao
- Division of Nutrition and Metabolism, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University, São Paulo, Brazil
| | | | | | - Helio Vannucchi
- Division of Medical Nutrition (Nutrology), São Paulo University, São Paulo, Brazil
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C-C chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model. PLoS One 2015; 10:e0120711. [PMID: 25816097 PMCID: PMC4376739 DOI: 10.1371/journal.pone.0120711] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 01/26/2015] [Indexed: 12/11/2022] Open
Abstract
Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.
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18
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Bonomini F, Rodella LF, Rezzani R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis 2015; 6:109-20. [PMID: 25821639 DOI: 10.14336/ad.2014.0305] [Citation(s) in RCA: 401] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 03/05/2014] [Indexed: 12/13/2022] Open
Abstract
The prevalence of the metabolic syndrome, a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart diseases. One of the defects in metabolic syndrome and its associated diseases is excess of reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process. In this article we review current understandings of oxidative stress in metabolic syndrome related disease and its possible contribution to accelerated senescence.
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Affiliation(s)
- Francesca Bonomini
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Luigi Fabrizio Rodella
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Rita Rezzani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
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19
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Lucchesi AN, Cassettari LL, Spadella CT. Alloxan-induced diabetes causes morphological and ultrastructural changes in rat liver that resemble the natural history of chronic fatty liver disease in humans. J Diabetes Res 2015; 2015:494578. [PMID: 25789328 PMCID: PMC4350960 DOI: 10.1155/2015/494578] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 02/03/2015] [Accepted: 02/03/2015] [Indexed: 12/15/2022] Open
Abstract
PURPOSE This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. METHODS Thirty nondiabetic control rats (NC) and 30 untreated diabetic (UD) rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. RESULTS UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. CONCLUSION Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.
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Affiliation(s)
- Amanda Natália Lucchesi
- Graduate Program in General Basis of Surgery, Faculty of Medicine, São Paulo State University (UNESP), 18618-970 Botucatu, SP, Brazil
| | | | - César Tadeu Spadella
- Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), 18618-970 Botucatu, SP, Brazil
- *César Tadeu Spadella:
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20
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Zigmond E, Tayer-Shifman O, Lalazar G, Ben Ya'acov A, Weksler-Zangen S, Shasha D, Sklair-Levy M, Zolotarov L, Shalev Z, Kalman R, Ziv E, Raz I, Ilan Y. β-glycosphingolipids ameliorated non-alcoholic steatohepatitis in the Psammomys obesus model. J Inflamm Res 2014; 7:151-8. [PMID: 25336983 PMCID: PMC4200037 DOI: 10.2147/jir.s50508] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that β-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with β-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of β-glucosylceramide, β-lactosylceramide, or a combination of both. β-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both β-glucosylceramide and β-lactosylceramide also decreased interferon (IFN)-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that β-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.
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Affiliation(s)
- Ehud Zigmond
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | | | - Gadi Lalazar
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | | | - David Shasha
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Miriam Sklair-Levy
- Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Lidya Zolotarov
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Zvi Shalev
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Rony Kalman
- Diabetes Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Ehud Ziv
- Diabetes Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Itamar Raz
- Diabetes Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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21
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Scalera A, Di Minno MND, Tarantino G. What does irritable bowel syndrome share with non-alcoholic fatty liver disease? World J Gastroenterol 2013; 19:5402-5420. [PMID: 24023483 PMCID: PMC3761093 DOI: 10.3748/wjg.v19.i33.5402] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/05/2013] [Accepted: 07/23/2013] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) are two very common diseases in the general population. To date, there are no studies that highlight a direct link between NAFLD and IBS, but some recent reports have found an interesting correlation between obesity and IBS. A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD, leading to an increased cardiovascular risk, and IBS, leading to microbial dysbiosis, impaired intestinal barrier and altered intestinal motility. It is not known when considering local and systemic inflammation/immune system activation, which one has greater importance in NAFLD and IBS pathogenesis. Also, the nervous system is implicated. In fact, inflammation participates in the development of mood disorders, such as anxiety and depression, characteristics of obesity and consequently of NAFLD and, on the other hand, in intestinal hypersensitivity and dysmotility.
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22
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Ziamajidi N, Khaghani S, Hassanzadeh G, Vardasbi S, Ahmadian S, Nowrouzi A, Ghaffari SM, Abdirad A. Amelioration by chicory seed extract of diabetes- and oleic acid-induced non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) via modulation of PPARα and SREBP-1. Food Chem Toxicol 2013; 58:198-209. [PMID: 23603006 DOI: 10.1016/j.fct.2013.04.018] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 03/30/2013] [Accepted: 04/05/2013] [Indexed: 12/14/2022]
Abstract
We evaluated the effect of chicory (Cichorium intybus L.) seed extract (CI) on hepatic steatosis caused by early and late stage diabetes in rats (in vivo), and induced in HepG2 cells (in vitro) by BSA-oleic acid complex (OA). Different dosages of CI (1.25, 2.5 and 5 mg/ml) were applied along with OA (1 mM) to HepG2 cells, simultaneously and non-simultaneously; and without OA to ordinary non-steatotic cells. Cellular lipid accumulation and glycerol release, and hepatic triglyceride (TG) content were measured. The expression levels of sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARα) were determined. Liver samples were stained with hematoxylin and eosin (H&E). Significant histological damage (steatosis-inflammation-fibrosis) to the cells and tissues and down-regulation of SREBP-1c and PPARα genes that followed steatosis induction were prevented by CI in simultaneous treatment. In non-simultaneous treatment, CI up-regulated the expression of both genes and restored the normal levels of the corresponding proteins; with a greater stimulating effect on PPARα, CI acted as a PPARα agonist. CI released glycerol from HepG2 cells, and targeted the first and the second hit phases of hepatic steatosis. A preliminary attempt to characterize CI showed caffeic acid, chlorogenic acid, and chicoric acid, among the constituents.
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Affiliation(s)
- Nasrin Ziamajidi
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Bonfrate L, Giuliante F, Palasciano G, Lamont JT, Portincasa P. Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis. Ann Hepatol 2013; 12:634-641. [PMID: 23813143 DOI: 10.1016/s1665-2681(19)31349-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation.
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Affiliation(s)
- L Bonfrate
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University Medical School, Bari, Italy
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Lucchesi AN, Freitas NTD, Cassettari LL, Marques SFG, Spadella CT. Diabetes mellitus triggers oxidative stress in the liver of alloxan-treated rats: a mechanism for diabetic chronic liver disease. Acta Cir Bras 2013; 28:502-8. [DOI: 10.1590/s0102-86502013000700005] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 06/24/2013] [Indexed: 01/05/2023] Open
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Grattagliano I, Diogo CV, Mastrodonato M, de Bari O, Persichella M, Wang DQH, Liquori A, Ferri D, Carratù MR, Oliveira PJ, Portincasa P. A silybin-phospholipids complex counteracts rat fatty liver degeneration and mitochondrial oxidative changes. World J Gastroenterol 2013; 19:3007-3017. [PMID: 23716980 PMCID: PMC3662940 DOI: 10.3748/wjg.v19.i20.3007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 11/06/2012] [Accepted: 11/11/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effectiveness of antioxidant compounds in modulating mitochondrial oxidative alterations and lipids accumulation in fatty hepatocytes. METHODS Silybin-phospholipid complex containing vitamin E (Realsil(®)) was daily administered by gavage (one pouch diluted in 3 mL of water and containing 15 mg vitamin E and 47 mg silybin complexed with phospholipids) to rats fed a choline-deprived (CD) or a high fat diet [20% fat, containing 71% total calories as fat, 11% as carbohydrate, and 18% as protein, high fat diet (HFD)] for 30 d and 60 d, respectively. The control group was fed a normal semi-purified diet containing adequate levels of choline (35% total calories as fat, 47% as carbohydrate, and 18% as protein). Circulating and hepatic redox active and nitrogen regulating molecules (thioredoxin, glutathione, glutathione peroxidase), NO metabolites (nitrosothiols, nitrotyrosine), lipid peroxides [malondialdehyde-thiobarbituric (MDA-TBA)], and pro-inflammatory keratins (K-18) were measured on days 0, 7, 14, 30, and 60. Mitochondrial respiratory chain proteins and the extent of hepatic fatty infiltration were evaluated. RESULTS Both diet regimens produced liver steatosis (50% and 25% of liver slices with CD and HFD, respectively) with no signs of necro-inflammation: fat infiltration ranged from large droplets at day 14 to disseminated and confluent vacuoles resulting in microvesicular steatosis at day 30 (CD) and day 60 (HFD). In plasma, thioredoxin and nitrosothiols were not significantly changed, while MDA-TBA, nitrotyrosine (from 6 ± 1 nmol/L to 14 ± 3 nmol/L day 30 CD, P < 0.001, and 12 ± 2 nmol/L day 60 HFD, P < 0.001), and K-18 (from 198 ± 20 to 289 ± 21 U/L day 30 CD, P < 0.001, and 242 ± 23 U/L day 60 HFD, P < 0.001) levels increased significantly with ongoing steatosis. In the liver, glutathione was decreased (from 34.0 ± 1.3 to 25.3 ± 1.2 nmol/mg prot day 30 CD, P < 0.001, and 22.4 ± 2.4 nmol/mg prot day 60 HFD, P < 0.001), while thioredoxin and glutathione peroxidase were initially increased and then decreased. Nitrosothiols were constantly increased. MDA-TBA levels were five-fold increased from 9.1 ± 1.2 nmol/g to 75.6 ± 5.4 nmol/g on day 30, P < 0.001 (CD) and doubled with HFD on day 60. Realsil administration significantly lowered the extent of fat infiltration, maintained liver glutathione levels during the first half period, and halved its decrease during the second half. Also, Realsil modulated thioredoxin changes and the production of NO derivatives and significantly lowered MDA-TBA levels both in liver (from 73.6 ± 5.4 to 57.2 ± 6.3 nmol/g day 30 CD, P < 0.01 and from 27.3 ± 2.1 nmol/g to 20.5 ± 2.2 nmol/g day 60 HFD, P < 0.01) and in plasma. Changes in mitochondrial respiratory complexes were also attenuated by Realsil in HFD rats with a major protective effect on Complex II subunit CII-30. CONCLUSION Realsil administration effectively contrasts hepatocyte fat deposition, NO derivatives formation, and mitochondrial alterations, allowing the liver to maintain a better glutathione and thioredoxin antioxidant activity.
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Grattagliano I, Ubaldi E, Napoli L, Marulli CF, Nebiacolombo C, Cottone C, Portincasa P. Utility of noninvasive methods for the characterization of nonalcoholic liver steatosis in the family practice. The "VARES" Italian multicenter study. Ann Hepatol 2013; 12:70-77. [PMID: 23293196 DOI: 10.1016/s1665-2681(19)31387-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
The diagnostic utilities of ultrasonography (US), fatty liver index (FLI) and an algorithm of nine serum markers (Fibromax) were evaluated in family practice to noninvasively characterize patients with nonalcoholic fatty liver disease (NAFLD). A multicenter study was conducted by enrolling 259 consecutively observed patients (age 51 ± 10 years) with clinical and ultrasonographic features of NAFLD . Patients had mild (16.2%), moderate (69.9%), or severe (13.9%) liver steatosis and 60.2% had hypertransaminasemia. The percent of patients with overweight, obesity, diabetes, hypertension, and dyslipidemia were 42.7%, 46.5% (4.2% severe obesity), 24.7%, 40.9%, and 56.4% , respectively. Lean patients (10.8%) had normal transaminases in two/thirds of the cases. A multivariate logistic regression (including age > 50 yrs, BMI > 30 kg/m2, HOMA > 3, and hypertransaminasemia) identified 12.3% of patients at risk for steatohepatitis. With a sensitivity of 50% and specificity of 94.7%, Fibromax identified 34 patients (13.1%) with likely advanced fibrosis and found that over 28% of patients with moderate (ultrasonographic) steatosis were likely to be carrying severe steatosis. Steatotest score was significantly associated with BMI, waist circumference, ALT, triglycerides, and FLI. Fibrotest correlated only with ALT. FLI identified 73.4% of patients as likely to be carrying a fatty liver. In conclusion, NAFLD should be systematically searched and characterized in all patients with metabolic disturbances and cardiovascular risk. Asymptomatic subjects at risk also should be screened for NAFLD. Fibromax is a promising noninvasive diagnostic tool in family medicine for identifying patients at risk for NAFLD who require targeted follow-up.
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Wu LH, Huang CC, Adhikarakunnathu S, San Mateo LR, Duffy KE, Rafferty P, Bugelski P, Raymond H, Deutsch H, Picha K, Ward CK, Alexoupolou L, Flavell RA, Mbow ML, Susulic VS. Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice. Metabolism 2012; 61:1633-45. [PMID: 22607770 DOI: 10.1016/j.metabol.2012.04.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 03/29/2012] [Accepted: 04/13/2012] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism. MATERIALS AND METHODS Wild type (WT) and TLR3 knock-out (TLR3(-/-)) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33 weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3. RESULTS TLR3(-/-) mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3(-/-) mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3(-/-) mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways. CONCLUSIONS TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.
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Affiliation(s)
- Linda H Wu
- Janssen Pharmaceutical Companies of Johnson & Johnson, USA.
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Grattagliano I, de Bari O, Bernardo TC, Oliveira PJ, Wang DQH, Portincasa P. Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. Clin Biochem 2012; 45:610-618. [PMID: 22484459 DOI: 10.1016/j.clinbiochem.2012.03.024] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Revised: 02/02/2012] [Accepted: 03/12/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Mitochondria play a major role in cell energy-generating processes and integrate several signalling pathways to control cellular life and death. DESIGN AND METHODS Several liver diseases are characterized by mitochondrial alterations which are directly or indirectly dependent on the activation of intracellular stress cascades or receptor-mediated pathways. This article examines the role of mitochondrial dysfunction in critical initiating or propagating events in fatty liver infiltration and nonalcoholic fatty liver disease (NAFLD). Genetic variants and the role of drug-induced toxicity have been considered. RESULTS Key alterations of mitochondrial physiology associated with hepatocyte fatty changes are described. The value of novel non-invasive diagnostic methods to detect mitochondrial metabolic alterations is also discussed. CONCLUSIONS Mitochondrial metabolic remodeling is a predominant factor in the appearance and perpetuation of hepatocyte fat accumulation. Non-invasive techniques to identify mitochondrial dysfunction and proper mitochondria protection are two necessary clinical steps for an efficient management of NAFLD.
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Affiliation(s)
- Ignazio Grattagliano
- Department of Interdisciplinary Medicine, Clinica Medica A. Murri, University of Bari Medical School, Bari, Italy.
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The crude extract from puerariae flower exerts antiobesity and antifatty liver effects in high-fat diet-induced obese mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:272710. [PMID: 22685484 PMCID: PMC3368216 DOI: 10.1155/2012/272710] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 03/28/2012] [Indexed: 12/15/2022]
Abstract
Kudzu, a leguminous plant, has long been used in folk medicine. In particular, its flowers are used in Japanese and Chinese folk medicine for treating hangovers. We focused on the flower of Kudzu (Puerariae thomsonii), and we previously reported the antiobesity effect of Puerariae thomsonii flower extract (PFE) in humans. In this study, we conducted an animal study to investigate the effect of PFE on visceral fat and hepatic lipid levels in mice with diet-induced obesity. In addition, we focused on gene expression profiles to investigate the antiobesity mechanism of PFE. Male C57BL/6J mice were fed a high-fat diet (HFD) or an HFD supplemented with 5% PFE for 14 days. PFE supplementation significantly reduced body weight and white adipose tissue (WAT) weight. Moreover, in the histological analysis, PFE supplementation improved fatty liver. Hepatic reverse transcription-polymerase chain reaction revealed that PFE supplementation downregulated acetyl-CoA carboxylase expression. For adipose tissue, the expressions of hormone-sensitive lipase in WAT and uncoupling protein 1 in brown adipose tissue (BAT) were significantly upregulated. These results suggest that PFE exerts antiobesity and antifatty liver effects in high-fat diet-induced obese mice through suppressing lipogenesis in the liver, stimulating lipolysis in WAT, and promoting thermogenesis in BAT.
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Shih PH, Hwang SL, Yeh CT, Yen GC. Synergistic effect of cyanidin and PPAR agonist against nonalcoholic steatohepatitis-mediated oxidative stress-induced cytotoxicity through MAPK and Nrf2 transduction pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:2924-2933. [PMID: 22364184 DOI: 10.1021/jf300005v] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is caused by an elevation in oxidative stress, which might further lead to hepatic fibrogenesis. Importantly, both peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2-related factor 2 (Nrf2) play roles in modulating oxidative stress-mediated hepatic dysfunction. The objective of this study was to investigate the mechanisms of the multifunctional effects of cyanidin on regulating antioxidant enzymes and oxidative stress-induced hepatotoxicity. The data indicated that cyanidin-mediated antioxidant enzyme expression involved the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways and Nrf2 activation. Furthermore, the synergistic effect of cyanidin and the PPAR agonist, troglitazone, on Nrf2-PPAR activation, was also observed. Besides, treatment of cyanidin and troglitazone abolished H₂O₂-induced downregulation of genes involved in lipid metabolism. In addition, H₂O₂-mediated cytotoxicity, which was caused by inducing ROS formation and apoptotic cell death, was also ameliorated upon cyanidin and troglitazone stimulation. In conclusion, mitogen-activated protein kinases (MAPKs) and the transcription factor Nrf2 played regulatory roles in cyanidin-mediated antioxidant enzyme activation. Furthermore, the combination of cyanidin and troglitazone activated PPARγ-Nrf2 and improved H₂O₂-mediated perturbation of genes involved in lipid metabolism. These data suggested that cyanidin and PPAR agonists might have synergistic benefits against metabolic dysfunction-related oxidative damage.
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Affiliation(s)
- Ping-Hsiao Shih
- Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan
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Al-Gayyar MMH, Shams MEE, Barakat EAME. Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease. PHARMACEUTICAL BIOLOGY 2012; 50:297-303. [PMID: 22103753 DOI: 10.3109/13880209.2011.604088] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in Egypt, in parallel with increasing obesity. NAFLD can lead to liver inflammation, fibrosis and cirrhosis. NAFLD appears tightly linked with metabolic syndrome (MetS). OBJECTIVE Examine the impact of dietary fish oil on human patients with MetS and NAFLD. MATERIALS AND METHODS One hundred and forty patients were enrolled in the current study and classified into two groups: patients with both MetS and NAFLD and patients with MetS alone. Sixty-four patients were treated with daily supplementation of 2 g of fish oil for 6 months. Markers of hyperlipidemia and oxidative stress, hydrogen peroxide (H(2)O(2)) and malondialdhyde (MDA), as well as proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were analyzed. RESULTS Patients without fish oil exhibited significant increases in triglycerides (TGs), low-density lipoprotein (LDL), H(2)O(2) and MDA that were associated with significantly elevated TNF-α and IL-6 compared to controls. Furthermore, patients with both NAFLD and MetS showed significant increase in H(2)O(2), MDA, TNF-α and IL-6 levels compared with MetS group (p < 0.05). Treatment with fish oil reduced serum level of TG, LDL-cholesterol (LDL-C), H(2)O(2), MDA, TNF-α and IL-6 levels in patients and did not affect the control levels. DISCUSSION AND CONCLUSION Patients with NAFLD had bad lipid profile through a mechanism that involved developed redox imbalance, characterized by boosted free-radical activity and lipid peroxidation enhancing the release of proinflammatory cytokines leading to increased MetS risk and liver damage. However, daily treatment of patients with fish oil for 6 months improved lipid profile and blocked the oxidative stress and cytokines release.
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Affiliation(s)
- Mohammed M H Al-Gayyar
- Department of Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt.
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de Castro GSF, dos Santos RA, Portari GV, Jordão AA, Vannucchi H. Omega-3 improves glucose tolerance but increases lipid peroxidation and DNA damage in hepatocytes of fructose-fed rats. Appl Physiol Nutr Metab 2012; 37:233-40. [PMID: 22360345 DOI: 10.1139/h11-154] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The high consumption of fructose is linked to the increase in various characteristics of the metabolic syndrome. Fish oil is beneficial for the treatment of these comorbidities, such as insulin resistance, dyslipidemia, and hepatic steatosis. The objective of this study was to evaluate the consequences of the administration of fish oil concomitant to fructose ingestion during the experiment (45 days) and during the final 15 days in high-fructose-fed rats. Male Wistar rats were divided into 5 groups: control; those receiving 10% fish oil (FO); those receiving 60% fructose (Fr); those receiving 60% fructose and 10% fish oil for 45 days (FrFO); and those receiving fructose plus soybean oil for 30 days and fish oil for the final 15 days of the study (FrFO15). There was an increase in triacylglycerol, serum total cholesterol, and hepatic volume in the Fr group. The FO and FrFO groups experienced an increase in lipid peroxidation and a decrease in serum reduced glutathione. The FrFO group suffered greater hepatic injury, with increased alanine aminotransferase levels and DNA damage. Marked n-3 incorporation occurred in the groups receiving fish oil, favoring a better response to the oral glucose tolerance test. Fructose induced comorbidities of the metabolic syndrome, and the use of fish oil promoted a better glucose tolerance, although it was accompanied by more hepatocyte damage.
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Chung MY, Oh DK, Lee KW. Hypoglycemic health benefits of D-psicose. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:863-9. [PMID: 22224918 DOI: 10.1021/jf204050w] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Diabetes is an emerging health problem worldwide. The incidence of type 2 diabetes has dramatically increased and is expected to increase more rapidly in the future. Most patients with type 2 diabetes suffer from obesity and diabetes-related complications, including cardiovascular disease and hepatic steatosis. It has been proposed that simple sugar consumption is one of the major risk factors in the development of diabetes. Hence, the replacement of sugars with a low glycemic response would be an effective strategy to prevent type 2 diabetes. Accumulating evidence demonstrates that D-psicose, which has 70% the sweetness of sucrose and no calories, is a functional sugar exerting several health benefits preventing the development of diabetes. Although D-psicose presents in small amounts in natural products, a recent new technique using biocatalyst sources enables large-scale D-psicose production. More importantly, several clinical and animal studies demonstrated that D-psicose has hypoglycemic, hypolipidemic, and antioxidant activities, which make it an ideal candidate for preventing diabetes and related health concerns. This review will summarize the protective effects of D-psicose against type 2 diabetes and its complications, suggesting its potential benefits as a sucrose substitute.
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Affiliation(s)
- Min-Yu Chung
- Center for Agricultural Biomaterials, Seoul National University, Seoul, South Korea
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Abstract
BACKGROUND Hepatic encephalopathy is a disorder of brain function as a result of liver failure and/or portosystemic shunt. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient's quality of life and daily functioning and represent a significant burden on health care resources. Probiotics are live microorganisms, which when administered in adequate amounts may confer a health benefit on the host. OBJECTIVES To quantify the beneficial and harmful effects of any probiotic in any dosage, compared with placebo or no intervention, or with any other treatment for patients with any grade of acute or chronic hepatic encephalopathy as assessed from randomised trials. SEARCH METHODS We searched the The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, conference proceedings, reference lists of included trials and the WHO international clinical trials registry until April 2011 registry platform to identify new and ongoing trials. SELECTION CRITERIA We included randomised trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in patients with hepatic encephalopathy. DATA COLLECTION AND ANALYSIS Three authors independently assessed the risk of bias of the included trials and extracted data on relevant outcomes, with differences resolved by consensus. We conducted random-effects model meta-analysis due to obvious heterogeneity of patients and interventions. A P value of 0.05 or less was defined as significant. Dichotomous outcomes are expressed as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS We included seven trials of which 550 participants were randomised. Four of the seven trials compared a probiotic with placebo or no treatment in 245 participants, another trial compared a probiotic with lactulose in 40 participants , and the remaining two trials compared a probiotic with both placebo and lactulose in 265 participants. Each trial used different types of probiotics. Duration of administration of the experimental intervention varied from 10 days to 180 days. Two trials were industry funded, and five were unclear about origin of funding. All trials had high risk of bias. When probiotics were compared with no treatment, there was no significant difference in all-cause mortality (2 trials, 105 participants; 1/57 (2%) versus 1/48 (2%): RR 0.72; 95% CI 0.08 to 6.60), lack of recovery (4 trials, 206 participants; 54/107 (50%) versus 68/99 (69%): RR 0.72; 95% CI 0.49 to 1.05), adverse events (3 trials, 145 participants; 2/77 (3%) versus 6/68 (9%): RR 0.34; 95% CI 0.08 to 1.42), quality of life (1 trial, 20 participants contributed to the physical quality of life measurement, 20 participants contributed to the mental quality of life: MD Physical 0.00; 95% CI -5.47 to 5.47; MD Mental 4.00; 95% CI -1.82 to 9.82), or change of/or withdrawal from treatment (3 trials, 175 participants; 11/92 (12%) versus 7/83 (8%): RR 1.28; 95% CI 0.52 to 3.19). No trial reported sepsis or duration of hospital stay as an outcome. Plasma ammonia concentration was significantly lower for participants treated with probiotic at one month (3 trials, 226 participants: MD -2.99 μmol/L; 95% CI -5.70 to -0.29) but not at two months (3 trials, 181 participants: MD -1.82 μmol/L; 95% CI -14.04 to 10.41). Plasma ammonia decreased the most in the participants treated with probiotic at three months (1 trial, 73 participants: MD -6.79 μmol/L; 95% CI -10.39 to -3.19). When probiotics were compared with lactulose no trial reported all-cause mortality, quality of life, duration of hospital stay, or septicaemia. There were no significant differences in lack of recovery (3 trials, 173 participants; 47/87 (54%) versus 44/86 (51%): RR 1.05; 95% CI 0.75 to 1.47), adverse events (2 trials, 111 participants; 3/56 (5%) versus 6/55 (11%): RR 0.57; 95% CI 0.06 to 5.74), change of/or withdrawal from treatment at one month (3 trials, 190 participants; 8/95 (8%) versus 7/95 (7%): RR 1.10; 95% CI 0.40 to 3.03), plasma ammonia concentration (2 trials, 93 participants: MD -6.61 μmol/L; 95% CI -30.05 to 16.84), or change in plasma ammonia concentration (1 trial, 77 participants: MD 1.16 μmol/L; 95% CI -1.96 to 4.28). AUTHORS' CONCLUSIONS The trials we located suffered from a high risk of systematic errors ('bias') and high risk of random errors ('play of chance'). While probiotics appear to reduce plasma ammonia concentration when compared with placebo or no intervention, we are unable to conclude that probiotics are efficacious in altering clinically relevant outcomes. Demonstration of unequivocal efficacy is needed before probiotics can be endorsed as effective therapy for hepatic encephalopathy. Further randomised clinical trials are needed.
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Affiliation(s)
- Richard G McGee
- Sydney School of Public Health, University of Sydney, Sydney, Australia.
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García-Cañaveras JC, Donato MT, Castell JV, Lahoz A. A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations. J Proteome Res 2011; 10:4825-34. [PMID: 21830829 DOI: 10.1021/pr200629p] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Steatosis, or excessive accumulation of lipids in the liver, is a generally accepted previous step to the development of more severe conditions like nonalcoholic steatohepatitis, fibrosis, and cirrhosis. We aimed to characterize the metabolic profile that defines simple steatosis in human tissue and to identify potential disturbances in the hepatic metabolism that could favor the switch to progressive liver damage. A total of 46 samples, 23 from steatotic and 23 from nonsteatotic human livers, were analyzed following a holistic LC-MS-based metabonomic analysis that combines RP and HILIC chromatographic separations. Multivariate statistical data analysis satisfactorily classified samples and revealed steatosis-associated biomarkers. Increased levels of bile acids and phospholipid degradation products, and decreased levels of antioxidant species, were found in steatotic livers, indicating disturbances in lipid and bile acid homeostasis and mitochondrial dysfunction. Changes in hypoxanthine, creatinine, glutamate, glutamine, or γ-glutamyl-dipeptides concentrations, suggestive of alterations in energy metabolism and amino acid metabolism and transport, were also found. The results show that the proposed analytical strategy is suitable to achieve a comprehensive metabolic profile of steatotic human liver tissue and provide new insights into the metabolic alterations occurring in fatty liver that could contribute to its predisposition to damage evolution.
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Affiliation(s)
- Juan C García-Cañaveras
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria-Fundación Hospital La Fe , Valencia, Spain
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Ai ZL, Zhu CH, Min M, Wang J, Lan CH, Fan LL, Sun WJ, Chen DF. The Role of Hepatic Liver X Receptor α-and Sterol Regulatory Element Binding Protein-1c-Mediated Lipid Disorder in the Pathogenesis of Non-Alcoholic Steatohepatitis in Rats. J Int Med Res 2011; 39:1219-29. [PMID: 21986124 DOI: 10.1177/147323001103900410] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Liver X receptor α (LXRα) and sterol regulatory element binding protein-1c (SREBP-1c) were studied in rats with non-alcoholic steatohepatitis (NASH) induced by a high-fat diet. Forty 5-week-old rats were fed either a high-fat diet ( n = 30) or a normal diet ( n = 10) for 9, 13 or 17 weeks. The mRNA and protein levels for LXRα and SREBP-1c were measured at each time point, as was fatty acid synthase (FAS) activity and the serum levels of free fatty acid (FFA) and triglyceride (TG). The mRNA and protein levels for LXRα and SREBP-1c, FAS activity and serum levels of FFA and TG all significantly increased from week 9 in the high-fat diet rats versus controls. In conclusion, a high-fat diet upregulates LXRα which, in turn, upregulates SREBP-1c, increasing the activity of FAS and FFA and accumulation of TG in hepatocytes. Thus, LXRα and SREBP-1c contribute to the development of NASH.
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Affiliation(s)
- Z-L Ai
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - C-H Zhu
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
- Department of Gastroenterology and Hepatology, Hospital 309 of the People's Liberation Army, Beijing, China
| | - M Min
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - J Wang
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - C-H Lan
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - L-L Fan
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - W-J Sun
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - D-F Chen
- Department of Gastroenterology and Hepatology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
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Chung MY, Park HJ, Manautou JE, Koo SI, Bruno RS. Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. J Nutr Biochem 2011; 23:361-7. [PMID: 21543212 DOI: 10.1016/j.jnutbio.2011.01.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2010] [Revised: 01/06/2011] [Accepted: 01/07/2011] [Indexed: 02/06/2023]
Abstract
Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.
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Affiliation(s)
- Min-Yu Chung
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
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Dietary α- and γ-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatory-related responses in an obese mouse model of nonalcoholic steatohepatitis. J Nutr Biochem 2011; 21:1200-6. [PMID: 20138495 DOI: 10.1016/j.jnutbio.2009.10.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 10/12/2009] [Accepted: 10/19/2009] [Indexed: 12/17/2022]
Abstract
Oxidative stress contributes towards the development of nonalcoholic steatohepatitis (NASH). Thus, antioxidants may decrease oxidative stress and ameliorate the events contributing to NASH. We hypothesized that α- or γ-tocopherol would protect against lipopolysaccharide (LPS)-triggered NASH in an obese (ob/ob) mouse model. Five-week-old obese mice (n=18/dietary treatment) were provided 15 mg/kg each of α- and γ-tocopherol or 500 mg/kg of α- or γ-tocopherol for 5-weeks. Then, all mice were injected ip once with LPS (250 μg/kg) before being sacrificed at 0, 1.5 or 6 h. Body weight and hepatic steatosis were unaffected by tocopherols and LPS. Hepatic α- and γ-tocopherol increased (P<.05) ~9.8- and 10-fold in respective tocopherol supplemented mice and decreased in response to LPS. LPS increased serum alanine aminotransferase (ALT) by 86% at 6 h and each tocopherol decreased this response by 29-31%. By 6 h, LPS increased hepatic malondialdehyde (MDA) and tumor necrosis factor-α by 81% and 44%, respectively, which were decreased by α- or γ-tocopherol. Serum ALT was correlated (P<.05) to hepatic tumor necrosis factor-α (r=0.585) and MDA (r=0.592), suggesting that inflammation and lipid peroxidation contributed to LPS-triggered hepatic injury. α- and γ-Tocopherol similarly attenuated LPS-triggered increases in serum free fatty acid, and α-tocopherol only maintained the LPS-triggered serum triacylglycerol responses at 6 h. These findings indicate that increasing hepatic α- or γ-tocopherol protected against LPS-induced NASH by decreasing liver damage, lipid peroxidation, and inflammation without affecting body mass or hepatic steatosis. Further study is needed to define the mechanisms by which these tocopherols protected against LPS-triggered NASH.
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Castro GSF, Cardoso JFR, Vannucchi H, Zucoloto S, Jordão AA. Fructose and NAFLD: metabolic implications and models of induction in rats. Acta Cir Bras 2011; 26 Suppl 2:45-50. [DOI: 10.1590/s0102-86502011000800009] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
PURPOSE: The increase in fructose consumption is paralleled by a higher incidence of obesity worldwide. This monosaccharide is linked to metabolic syndrome, being associated with hypertriglyceridemia, hypertension, insulin resistance and diabetes mellitus. It is metabolized principally in the liver, where it can be converted into fatty acids, which are stored in the form of triglycerides leading to NAFLD. Several models of NAFLD use diets high in simple carbohydrates. Thus, this study aimed to describe the major metabolic changes caused by excessive consumption of fructose in humans and animals and to present liver abnormalities resulting from high intakes of fructose in different periods of consumption and experimental designs in Wistar rats. METHODS: Two groups of rats were fasted for 48 hours and reefed for 24 or 48 hours with a diet containing 63% fructose. Another group of rats was fed an diet with 63% fructose for 90 days. RESULTS: Refeeding for 24 hours caused accumulation of large amounts of fat, compromising 100% of the hepatocytes. The amount of liver fat in animals refed for 48 hours decreased, remaining mostly in zone 2 (medium-zonal). In liver plates of Wistar rats fed 63% fructose for 45, 60 and 90 days it's possible to see that there is an increase in hepatocytes with fat accumulation according to the increased time; hepatic steatosis, however, is mild, compromising about 20% of the hepatocytes. CONCLUSIONS: Fructose is highly lipogenic, however the induction of chronic models in NAFLD requires long periods of treatment. The acute supply for 24 or 48 hours, fasted rats can cause big changes, liver steatosis with macrovesicular in all lobular zones.
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Sakaguchi S, Takahashi S, Sasaki T, Kumagai T, Nagata K. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab Pharmacokinet 2010; 26:30-46. [PMID: 21150132 DOI: 10.2133/dmpk.dmpk-10-rv-087] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Growing evidence indicates that the innate immune system and oxidative stress caused by gut-derived endotoxins play a key role in alcoholic liver disease (ALD). Intracellular mechanisms associated with endotoxin-induced signaling play a crucial role in the initiation and progression of ALD. It is now widely accepted that activation of the innate immune system and increased release of pro-inflammatory cytokines and other mediators play an important role in the development of ALD. Accumulating evidence suggests that alcohol-mediated upregulation of CYP2E1 expression may initiate lipid peroxidation via reactive oxygen species. Non-alcoholic steatohepatitis (NASH) is a liver disease characterized by histopathological features similar to those observed in ALD, but in the absence of significant alcohol consumption. Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into "first and second hits." This model considered the development of steatosis to be the "first hit," increasing the sensitivity of the liver to the putative "second hit," leading to hepatocyte injury, inflammation, and oxidative stress. We have emphasized the important role of gut-derived bacterial toxins, the innate immune system, and oxidative stress in the common pathogenic mechanism in ALD and NASH progression.
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Affiliation(s)
- Shuhei Sakaguchi
- Department of Environmental and Health Science, Tohoku Pharmaceutical University, Sendai, Japan.
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Fujimoto M, Tsuneyama K, Kinoshita H, Goto H, Takano Y, Selmi C, Keen CL, Gershwin ME, Shimada Y. The traditional Japanese formula keishibukuryogan reduces liver injury and inflammation in patients with nonalcoholic fatty liver disease. Ann N Y Acad Sci 2010; 1190:151-8. [PMID: 20388146 DOI: 10.1111/j.1749-6632.2009.05265.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Kampo formula keishibukuryogan (KBG, Guizhifulingwan) is frequently used in traditional Japanese and Chinese medicine to treat several symptoms and manifests anti-inflammatory and scavenging effects. Nonalcoholic fatty liver disease (NAFLD) is a common manifestation of the metabolic syndrome and has the potential to evolve to liver cirrhosis through chronic inflammation and steatohepatisis (NASH). We have recently reported the KBG significant effectiveness on liver injury in a NASH animal model that prompted us to prescribe to KBG (TJ-25). We performed a retrospective study and reviewed the charts of outpatients who were prescribed KBG for 8-12 weeks due to non-liver-related symptoms (n= 11) over the past year to evaluate the clinical outcome. In six of these cases, biochemical and ultrasound signs of NAFLD were observed. KBG led to a significant reduction in liver injury tests and blood cholesterol but had no effects on body weight in all NAFLD cases. Further, liver tests and lipid profiles returned to baseline values when KBG treatment was stopped. On the basis of data on a small number of subjects, we suggest that the use of KBG is a safe complementary treatment in patients with NAFLD. While it is unlikely that Kampo formulas may substitute the current nutritional approaches to the metabolic syndrome, future studies should address the possibility of an additive effect, possibly through anti-inflammatory mechanisms.
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Affiliation(s)
- Makoto Fujimoto
- Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Cariello R, Federico A, Sapone A, Tuccillo C, Scialdone VR, Tiso A, Miranda A, Portincasa P, Carbonara V, Palasciano G, Martorelli L, Esposito P, Cartenì M, Del Vecchio Blanco C, Loguercio C. Intestinal permeability in patients with chronic liver diseases: Its relationship with the aetiology and the entity of liver damage. Dig Liver Dis 2010; 42:200-204. [PMID: 19502117 DOI: 10.1016/j.dld.2009.05.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Revised: 04/30/2009] [Accepted: 05/01/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Alteration in intestinal permeability may be an important factor in the pathogenesis of both the progression of some chronic liver diseases and the onset of some complications in patients with liver cirrhosis. AIMS To investigate the relationships between intestinal permeability, portal hypertension, alcohol use, plasma levels of pro-inflammatory cytokines, and nitric oxide, expressed as s-nitrosothiols, and nitrite levels in patients with various types and degrees of chronic liver diseases. METHODS 134 healthy volunteers and 83 patients with chronic liver damage entered the study. Intestinal permeability was assessed with the lactulose/mannitol test. Plasma levels of tumour necrosis factor-alpha, interleukin-6, and nitrite and total s-nitrosothiols were determined. RESULTS Intestinal permeability was altered in patients with advanced liver disease and impaired in 15-35% of patients without cirrhosis. Independent factors for intestinal permeability alteration were age, portal hypertension, alcohol use, and diabetes. Plasma levels of inflammatory cytokines and nitrosothiols were significantly higher in patients with altered intestinal permeability. CONCLUSIONS An intestinal permeability evaluation in patients with chronic liver diseases might clarify the significance of intestinal permeability in the pathophysiology of both the progression of liver damage, and the occurrence of complications that accompany liver cirrhosis.
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Affiliation(s)
- Rita Cariello
- Department of Experimental Medicine, Second University of Naples, Italy
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Fukunishi S, Nishio H, Fukuda A, Takeshita A, Hanafusa T, Higuchi K, Suzuki K. Development of Fibrosis in Nonalcoholic Steatosis through Combination of a Synthetic Diet Rich in Disaccharide and Low-Dose Lipopolysaccharides in the Livers of Zucker (fa/fa) Rats. J Clin Biochem Nutr 2009; 45:322-8. [PMID: 19902023 PMCID: PMC2771254 DOI: 10.3164/jcbn.09-50] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2009] [Accepted: 06/03/2009] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) can develop into end-stage disease such as cryptogenic cirrhosis and hepatocellular carcinoma. Hence, it is important to understand the pathogenesis of NASH. In general, the "two-hit theory" has prevailed as a pathogenic mechanism of NASH. According to this theory, lipopolysaccharides (LPS) contained in normal portal blood are the "second hit," but their role is not completely understood. Based on this theory, we evaluated the role of LPS in NASH pathogenesis. For the first hit to develop metabolic abnormalities, a synthetic diet rich in disaccharide (synthetic diet: 12.1 cal% disaccharide) was fed to Zucker (fa/fa) rats for 12 weeks. For the second hit, 100 microg/kg LPS was injected intraperitoneally once daily for 2 weeks. Synthetic diet-fed rats treated with LPS showed an increase in the triglyceride content and higher expression of profibrogenic mRNAs in the liver. Plasma alanine aminotransferase levels were significantly elevated using this protocol. Furthermore, histological examination demonstrated that this protocol induced mild hepatic fibrosis and focal necrosis in the livers of all rats. Synthetic diet-fed Zucker (fa/fa) rats treated with LPS could be useful for understanding the development of hepatic fibrosis in the two-hit theory.
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Affiliation(s)
- Shinya Fukunishi
- Department of Legal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
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Grattagliano I, Bonfrate L, Diogo CV, Wang HH, Wang DQH, Portincasa P. Biochemical mechanisms in drug-induced liver injury: certainties and doubts. World J Gastroenterol 2009; 15:4865-4876. [PMID: 19842215 PMCID: PMC2764962 DOI: 10.3748/wjg.15.4865] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2009] [Revised: 09/04/2009] [Accepted: 09/11/2009] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O(2) supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca(2+)-dependent ATPase, reduced capability to sequester Ca(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
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Syn WK, Yang L, Chiang DJ, Qian Y, Jung Y, Karaca G, Choi SS, Witek RP, Omenetti A, Pereira TA, Diehl AM. Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice. Liver Int 2009; 29:1262-72. [PMID: 19490416 PMCID: PMC3610179 DOI: 10.1111/j.1478-3231.2009.02036.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD). DESIGN/INTERVENTION Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months. MAIN OUTCOME MEASURES Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis. RESULTS High-fat diets induced comparable obesity, hepatic steatosis and insulin resistance in the two strains. Compared with BL6 mice, 129/SVJ mice had impaired induction of antioxidant genes, generated three- to four-fold more free radicals and exhibited two-fold greater induction of profibrogenic cytokines (interleukin-4 and transforming growth factor-beta1) and fibrosis-related genes (fibronectin and tissue inhibitor of metalloproteinase-1) (all P<0.05 for 129 vs BL6). Surprisingly, however, induction of collagen I alpha1 mRNA and accumulation of Sirius red-stained fibrils and hepatic hydroxyproline were similar in BL6 and 129/SVJ mice, and although patchy sinusoidal fibrosis emerged in both strains, neither developed bridging fibrosis. CONCLUSIONS Although BL6 and 129/SVJ mice with diet-induced obesity, insulin resistance and steatosis differed with respect to several factors that are thought to influence human NAFLD progression, they developed comparable liver fibrosis. Moreover, none of the risk factors for NAFLD-related cirrhosis in humans, including obesity, insulin resistance, chronic inflammatory and oxidant stress, steatohepatitis or activation of fibrogenic genes, proved to be sufficient to cause cirrhosis in these mice, even when exposure to one or more of these insults was very prolonged.
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Affiliation(s)
- Wing-Kin Syn
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Liu Yang
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Dian Jung Chiang
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Yue Qian
- Division of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA
| | - Youngmi Jung
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Gamze Karaca
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Steve S. Choi
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Rafal P. Witek
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Alessia Omenetti
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Thiago A. Pereira
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Anna Mae Diehl
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
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Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21:673-680. [PMID: 19318971 DOI: 10.1097/meg.0b013e32831bc3d6] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Natural killer T (NKT) cells have been recently reported to concern with various lipid disorders. The role of NKT cells in the hepatic lipid disorder, nonalcoholic fatty liver disease (NAFLD), has, however, not yet been clarified. To assess the role of NKT cells in the pathogenesis of NAFLD, we analyzed the composition and function of liver-infiltrating cells isolated from liver biopsy specimens of patients with NAFLD. METHODS Specimens from 62 patients with NAFLD were studied, and 54 specimens among them reacted immunohistochemically with monoclonal antibodies against various surface markers. Moreover, using flow cytometry, we analyzed surface markers and intracytoplasmic cytokines of intrahepatic CD3+CD56+ cells in 12 patients among them. RESULTS Among the various populations of liver-infiltrating cells, only the numbers of CD56+ cells were significantly increased as NAFLD disease activity (NAFLD activity score, NAS) increased. Furthermore, expression of CD1d, a ligand for NKT cells, was also increased in NAFLD as NAS increased. Flow cytometric analysis showed that most CD56+ cells were Valpha24+ NKT cells, which produced more IFN-gamma and IL-4 as NAS increased. CONCLUSION Intrahepatic CD3+CD56+ NKT cells are increased in NAFLD as NAS increased. These cells may enhance disease activity through cytokine production after the recognition of lipid antigens presented with CD1d in livers of NAFLD.
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Affiliation(s)
- Kazuto Tajiri
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, Szabo G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009; 49:989-97. [PMID: 19115316 PMCID: PMC3756672 DOI: 10.1002/hep.22711] [Citation(s) in RCA: 203] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its advanced stage, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease in the United States. NASH features the metabolic syndrome, inflammation, and fibrosis. Probiotics exhibit immunoregulatory and anti-inflammatory activity. We tested the hypothesis that probiotic VSL#3 may ameliorate the methionine-choline-deficient (MCD) diet-induced mouse model of NASH. MCD diet resulted in NASH in C57BL/6 mice compared to methionine-choline-supplemented (MCS) diet feeding evidenced by liver steatosis, increased triglycerides, inflammatory cell accumulation, increased tumor necrosis factor alpha levels, and fibrosis. VSL#3 failed to prevent MCD-induced liver steatosis or inflammation. MCD diet, even in the presence of VSL#3, induced up-regulation of serum endotoxin and expression of the Toll-like receptor 4 signaling components, including CD14 and MD2, MyD88 adaptor, and nuclear factor kappaB activation. In contrast, VSL#3 treatment ameliorated MCD diet-induced liver fibrosis resulting in diminished accumulation of collagen and alpha-smooth muscle actin. We identified increased expression of liver peroxisome proliferator-activated receptors and decreased expression of procollagen and matrix metalloproteinases in mice fed MCD+VSL#3 compared to MCD diet alone. MCD diet triggered up-regulation of transforming growth factor beta (TGFbeta), a known profibrotic agent. In the presence of VSL#3, the MCD diet-induced expression of TGFbeta was maintained; however, the expression of Bambi, a TGFbeta pseudoreceptor with negative regulatory function, was increased. In summary, our data indicate that VSL#3 modulates liver fibrosis but does not protect from inflammation and steatosis in NASH. The mechanisms of VSL#3-mediated protection from MCD diet-induced liver fibrosis likely include modulation of collagen expression and impaired TGFbeta signaling.
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Affiliation(s)
- Arumugam Velayudham
- Department of Medicine, Liver Center, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA
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Grattagliano I, Palmieri VO, Portincasa P, Moschetta A, Palasciano G. Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem 2008; 19:491-504. [PMID: 17855068 DOI: 10.1016/j.jnutbio.2007.06.011] [Citation(s) in RCA: 201] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2007] [Revised: 06/05/2007] [Accepted: 06/18/2007] [Indexed: 01/18/2023]
Abstract
Although the biochemical steps linking insulin resistance with the metabolic syndrome have not been completely clarified, mounting experimental and clinical evidence indicate oxidative stress as an attractive candidate for a central pathogenic role since it potentially explains the appearance of all risk factors and supports the clinical manifestations. In fact, metabolic syndrome patients exhibit activation of biochemical pathways leading to increased delivery of reactive oxygen species, decreased antioxidant protection and increased lipid peroxidation. The described associations between increased abdominal fat storage, liver steatosis and systemic oxidative stress, the diminished concentration of nitric oxide derivatives and antioxidant vitamins and the endothelial oxidative damages observed in subjects with the metabolic syndrome definitively support oxidative stress as the common second-level event in a unifying pathogenic view. Moreover, it has been observed that oxidative stress regulates the expression of genes governing lipid and glucose metabolism through activation or inhibition of intracellular sensors. Diet constituents can modulate redox reactions and the oxidative stress extent, thus also acting on nuclear gene expression. As a consequence of the food-gene interaction, metabolic syndrome patients may express different disease features and extents according to the different pathways activated by oxidative stress-modulated effectors. This view could also explain family differences and interethnic variations in determining risk factor appearance. This review mechanistically focused on oxidative stress events leading to individual disease factor appearance in metabolic syndrome patients and their setting for a more helpful clinical approach.
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Affiliation(s)
- Ignazio Grattagliano
- Department of Internal Medicine and Public Medicine, University Medical School of Bari, Clinica Medica "A. Murri," 70124 Bari, Italy
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Grattagliano I, Caraceni P, Calamita G, Ferri D, Gargano I, Palasciano G, Portincasa P. Severe liver steatosis correlates with nitrosative and oxidative stress in rats. Eur J Clin Invest 2008; 38:523-530. [PMID: 18578693 DOI: 10.1111/j.1365-2362.2008.01963.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Little is known about nitric oxide (NO) metabolism and redox changes with hepatocyte adipocytic transformation. The aims of this study were to investigate the changes occurring in plasma and hepatic NO metabolites and redox balance in a rat experimental model of simple fatty liver, and to relate plasma with hepatic and mitochondrial changes at different degrees of steatosis. MATERIALS AND METHODS Circulating and hepatic redox active and nitrogen regulating molecules thioredoxin, glutathione, protein thiols (PSH), mixed disulfides (PSSG), NO metabolites nitrosothiols, nitrite plus nitrate (NOx), and lipid peroxides (TBARs) were measured in rats fed a choline deprived (CD) diet for 30 days. RESULTS At histology, the CD diet resulted in hepatocellular steatosis (75% of liver weight at day 30) with no signs of necro-inflammation. In plasma, thioredoxin, nitrosothiols and NOx were unchanged, while TBARs levels increased significantly and were positively related with hepatic TBARs (r = 0.87, P < 0.001) and lipid content (r = 0.90, P < 0.001). In the liver, glutathione initially increased (day 3) and then decreased. From day 14, PSH decreased and NO derivatives increased. Thioredoxin 1 had initially increased (days 7-14) and then decreased. In the mitochondria, on day 14, nitrosothiols were inversely related to thioredoxin 2 (r = 0.988, P < 0.05); on day 30, PSH were decreased by 70%, PSSG were doubled and related with nitrosothiols levels (r = 0.925, P < 0.001). CONCLUSION Adipocytic transformation of hepatocytes is accompanied by major interrelated modifications of redox parameters and NO metabolism especially at mitochondrial level, suggesting an early adaptive protective response but also an increased predisposition towards pro-oxidant insults.
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Affiliation(s)
- I Grattagliano
- Section of Internal Medicine, DIMIMP, University of Bari, Bari, Italy
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Federico A, Niosi M, Vecchio Blanco CD, Loguercio C. Emerging drugs for non-alcoholic fatty liver disease. Expert Opin Emerg Drugs 2008; 13:145-58. [PMID: 18321154 DOI: 10.1517/14728214.13.1.145] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a condition of emerging relevance that includes different forms of chronic liver damage, from a simple fatty infiltration (steatosis) of hepatocytes to steatohepatitis (NASH) with fibrosis. This last form may evolve to cirrhosis and hepatocellular carcinoma. OBJECTIVE To discuss therapeutic management of NAFLD. Theoretically, only patients with non-alcoholic steatohepatitis (NASH) need to be treated, as only NASH may evolve to cirrhosis. Differentiation between steatosis and NASH currently requires a liver biopsy. METHODS We discuss different therapeutic approaches proposed in literature for patients with NAFLD. RESULTS The treatment of associated conditions leads to an improvement of NAFLD and NASH. No specific drug is actually present to treat liver steatosis or NASH. CONCLUSIONS The treatment of NAFLD depends on the individual characteristics of each patient. Diet and physical exercise may be considered a basal universal approach. Future research will discover possible specific liver drugs.
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