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Comeglio P, Guarnieri G, Filippi S, Cellai I, Acciai G, Holyer I, Zetterberg F, Leffler H, Kahl-Knutson B, Sarchielli E, Morelli A, Maggi M, Slack RJ, Vignozzi L. The galectin-3 inhibitor selvigaltin reduces liver inflammation and fibrosis in a high fat diet rabbit model of metabolic-associated steatohepatitis. Front Pharmacol 2024; 15:1430109. [PMID: 39144627 PMCID: PMC11322497 DOI: 10.3389/fphar.2024.1430109] [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: 05/09/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
Introduction Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH). Methods Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression. Results Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease. Discussion Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.
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Affiliation(s)
- Paolo Comeglio
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Giulia Guarnieri
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Sandra Filippi
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Ilaria Cellai
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Gabriele Acciai
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | | | | | | | | | - Erica Sarchielli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Annamaria Morelli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Mario Maggi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Rome, Italy
| | | | - Linda Vignozzi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Rome, Italy
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Zhu J, Zhou T, Menggen M, Aimulajiang K, Wen H. Ghrelin regulating liver activity and its potential effects on liver fibrosis and Echinococcosis. Front Cell Infect Microbiol 2024; 13:1324134. [PMID: 38259969 PMCID: PMC10800934 DOI: 10.3389/fcimb.2023.1324134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Ghrelin widely exists in the central nervous system and peripheral organs, and has biological activities such as maintaining energy homeostasis, regulating lipid metabolism, cell proliferation, immune response, gastrointestinal physiological activities, cognition, memory, circadian rhythm and reward effects. In many benign liver diseases, it may play a hepatoprotective role against steatosis, chronic inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress and apoptosis, and improve liver cell autophagy and immune response to improve disease progression. However, the role of Ghrelin in liver Echinococcosis is currently unclear. This review systematically summarizes the molecular mechanisms by which Ghrelin regulates liver growth metabolism, immune-inflammation, fibrogenesis, proliferation and apoptosis, as well as its protective effects in liver fibrosis diseases, and further proposes the role of Ghrelin in liver Echinococcosis infection. During the infectious process, it may promote the parasitism and survival of parasites on the host by improving the immune-inflammatory microenvironment and fibrosis state, thereby accelerating disease progression. However, there is currently a lack of targeted in vitro and in vivo experimental evidence for this viewpoint.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Pourreza S, Azar PS, Sanaie S, Noshadi N, Jalali S, Niazkar HR, karimi A, Vajdi M. Therapeutic Effects and Mechanisms of Action of Garlic ( Allium sativum) on Nonalcoholic Fatty Liver Disease: A Comprehensive Systematic Literature Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:6960211. [PMID: 37377647 PMCID: PMC10292950 DOI: 10.1155/2022/6960211] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/02/2022] [Accepted: 08/25/2022] [Indexed: 04/16/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is globally the leading cause of hepatic dysfunction. Garlic has many physiological benefits, including anti-inflammatory, antioxidant, anticancer, lipid-lowering, and antidiabetes effects. The present study aimed to systematically review the effects of garlic (Allium sativum) and its mechanisms of function in managing NAFLD and its associated complications. The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements were applied to perform the study (CRD42021289348). The Scopus, Embase, Web of Science, Cochrane PubMed, and Google Scholar databases were searched until February 2022. According to the inclusion criteria, finally, 12 studies were entered into the study. The evidence provided in the study revealed that garlic could regulate the development of NAFLD via several mechanisms of action, such as lowering body weight, modulating lipid and glucose metabolism, and reducing inflammation and oxidative stress (OS). Overall, the beneficial effects of garlic in the treatment of NAFLD make it a potential therapeutic and efficient agent in managing NAFLD and its related risk factors. There is an insufficient number of clinical trials addressing the effects of garlic in humans; therefore, conducting more human research in the future is recommended.
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Affiliation(s)
- Sanaz Pourreza
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, University of Medical Sciences, Tehran, Iran
| | - Pouria Sefidmooye Azar
- Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nooshin Noshadi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeedeh Jalali
- Department of Clinical Nutrition, School of Nutrition and Food Science, University of Medical Sciences, Shiraz, Iran
| | - Hamid Reza Niazkar
- Breast Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arash karimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
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Gupta B, Rai R, Oertel M, Raeman R. Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids. Semin Liver Dis 2022; 42:122-137. [PMID: 35738255 PMCID: PMC9307091 DOI: 10.1055/s-0042-1748037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.
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Affiliation(s)
- Biki Gupta
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ravi Rai
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Reben Raeman
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania,Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Lesmana CRA, Kencana Y, Rinaldi I, Kurniawan J, Hasan I, Sanityoso Sulaiman A, Gani RA. Diagnostic Value of Neutrophil to Lymphocyte Ratio in Non-Alcoholic Fatty Liver Disease Evaluated Using Transient Elastography (TE) with Controlled Attenuated Parameter (CAP). Diabetes Metab Syndr Obes 2022; 15:15-22. [PMID: 35023936 PMCID: PMC8743379 DOI: 10.2147/dmso.s330526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/30/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease with excessive fat accumulation in the liver. Transient elastography (TE) with controlled attenuation parameter (CAP) is a device and method to examine the degree of fibrosis and steatosis. However, this device is not widely available across Indonesia. Neutrophil and lymphocyte ratio (NLR) is a simple marker for inflammation, which has a potency to predict disease outcome. This study aims to know the diagnostic value of NLR as the indicator of steatosis and fibrosis severity. METHODS This was a cross-sectional study with consecutive sample collection. We used secondary data from medical records, starting from 2016 to 2018. A descriptive and data analysis, including correlation test, multivariate linear regression, t-test, receiver operating curve (ROC) and area under the curve (AUC) were done to find out the outcome of the study. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) Version 20.0 (SPSS Inc, Chicago, Illinois). A P value <0.05 was considered as statistically significant. RESULTS Out of 106 subjects, 62.3% patients were women with the mean of age 57.29 years old and 77.4% had metabolic syndrome. Most patients had moderate to severe steatosis degree (66%) with the mean of TE mean 6.14 (2.8-18.2) kPa. There was a positive correlation between CAP and TE compared with NLR with r = 0.648 (p < 0.001) and r = 0.621 (p < 0.001), respectively. The use of RNL to assess moderate-severe steatosis has a cutoff point of 1.775 with sensitivity, specificity, PPV and NPV, respectively, at 81.5%, 80.6%, 89.1%, and 69.1%; cutoff point 2.150 to assess significant fibrosis with sensitivity, specificity, PPV and NPV of 92.3%, 87.5%, 70.6%, and 97.2%, respectively. CONCLUSION NLR has a positive and significant correlation with the degree of steatosis and fibrosis with high sensitivity and specificity as evaluated by TE/CAP.
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Affiliation(s)
- Cosmas Rinaldi Adithya Lesmana
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| | - Yoppi Kencana
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Ikhwan Rinaldi
- Department of Internal Medicine, Haematology and Oncology Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Juferdy Kurniawan
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Irsan Hasan
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Andri Sanityoso Sulaiman
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Rino Alvani Gani
- Department of Internal Medicine, Hepatobiliary Division, Dr. Cipto Mangunkusumo National General Hospital, Universitas Indonesia, Jakarta, Indonesia
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Comeglio P, Sarchielli E, Filippi S, Cellai I, Guarnieri G, Morelli A, Rastrelli G, Maseroli E, Cipriani S, Mello T, Galli A, Bruno BJ, Kim K, Vangara K, Papangkorn K, Chidambaram N, Patel MV, Maggi M, Vignozzi L. Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model. J Endocrinol Invest 2021; 44:2175-2193. [PMID: 33586025 PMCID: PMC8421272 DOI: 10.1007/s40618-021-01522-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/27/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. METHODS Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson's trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. RESULTS Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. CONCLUSIONS Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.
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Affiliation(s)
- P Comeglio
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - E Sarchielli
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - S Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - I Cellai
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - G Guarnieri
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - A Morelli
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - G Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - E Maseroli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - S Cipriani
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - T Mello
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - A Galli
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - B J Bruno
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - K Kim
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - K Vangara
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | | | | | - M V Patel
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - M Maggi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Rome, Italy
| | - L Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Rome, Italy.
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Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer's disease? Anal Biochem 2021; 636:114387. [PMID: 34537182 DOI: 10.1016/j.ab.2021.114387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/27/2021] [Accepted: 09/15/2021] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease, which has been classified as an emerging epidemic not only confined to liver-related morbidity and mortality. It is also becoming apparent that NAFLD is associated with moderate cerebral dysfunction and cognitive decline. A possible link between NAFLD and Alzheimer's disease (AD) has only recently been proposed due to the multiple shared genes and pathological mechanisms contributing to the development of these conditions. Although AD is a progressive neurodegenerative disease, the exact pathophysiological mechanism remains ambiguous and similarly to NAFLD, currently available pharmacological therapies have mostly failed in clinical trials. In addition to the usual suspects (inflammation, oxidative stress, blood-brain barrier alterations and ageing) that could contribute to the NAFLD-induced development and progression of AD, changes in the vasculature, cerebral perfusion and waste clearance could be the missing link between these two diseases. Here, we review the most recent literature linking NAFLD and AD, focusing on cerebrovascular alterations and the brain's clearance system as risk factors involved in the development and progression of AD, with the aim of promoting further research using neuroimaging techniques and new mechanism-based therapeutic interventions.
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Srinivas AN, Suresh D, Santhekadur PK, Suvarna D, Kumar DP. Extracellular Vesicles as Inflammatory Drivers in NAFLD. Front Immunol 2021; 11:627424. [PMID: 33603757 PMCID: PMC7884478 DOI: 10.3389/fimmu.2020.627424] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease in most parts of the world affecting one-third of the western population and a growing cause for end-stage liver diseases such as hepatocellular carcinoma (HCC). Majorly driven by obesity and diabetes mellitus, NAFLD is more of a multifactorial disease affected by extra-hepatic organ crosstalk. Non-alcoholic fatty liver (NAFL) progressed to non-alcoholic steatohepatitis (NASH) predisposes multiple complications such as fibrosis, cirrhosis, and HCC. Although the complete pathogenic mechanisms of this disease are not understood, inflammation is considered as a key driver to the onset of NASH. Lipotoxicity, inflammatory cytokines, chemokines, and intestinal dysbiosis trigger both hepatic and systemic inflammatory cascades simultaneously activating immune responses. Over a few years, extracellular vesicles studied extensively concerning the pathobiology of NAFLD indicated it as a key modulator in the setting of immune-mediated inflammation. Exosomes and microvesicles, the two main types of extracellular vesicles are secreted by an array of most mammalian cells, which are involved mainly in cell-cell communication that are unique to cell type. Various bioactive cargoes containing extracellular vesicles derived from both hepatic and extrahepatic milieu showed critical implications in driving steatosis to NASH reaffirming inflammation as the primary contributor to the whole process. In this mini-review, we provide brief insights into the inflammatory mediators of NASH with special emphasis on extracellular vesicles that acts as drivers of inflammation in NAFLD.
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Affiliation(s)
- Akshatha N Srinivas
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, India
| | - Diwakar Suresh
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, India
| | - Prasanna K Santhekadur
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, India
| | - Deepak Suvarna
- Department of Gastroenterology, JSS Medical College and Hospital, JSS Academy of Higher Education and Research, Mysuru, India
| | - Divya P Kumar
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, Mysuru, India
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Does adipose tissue inflammation drive the development of non-alcoholic fatty liver disease in obesity? Clin Res Hepatol Gastroenterol 2020; 44:394-402. [PMID: 32044284 DOI: 10.1016/j.clinre.2019.10.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 09/09/2019] [Accepted: 10/04/2019] [Indexed: 02/06/2023]
Abstract
Obesity, an increasingly common problem in modern societies, is associated with acquired metabolic disturbances. In this perspective, the development of insulin resistance is now recognized to be initiated by inflammation of the adipose tissue, but the events that lead to this inflammation are still vague. Furthermore, visceral adipose tissue plays a significant role in obesity pathophysiology and in its clinical effects, such as non-alcoholic fatty liver disease (NAFLD). Among the possible mechanisms linking NAFLD and obesity, we focused on Visfatin/NAMPT, mostly produced by macrophages infiltrated in adipose tissue and a biomarker of the inflammatory cascade affecting hepatic inflammation in NAFLD. We also addressed the signalling pathway triggered by the binding of VEGF-B to its receptor, which mediates lipid fluxes throughout the body, being a promising target to prevent ectopic lipid accumulation. We reviewed the available literature on the topic and we suggest a crosstalk between adipose tissue inflammation and NAFLD in order to provide new insights about the putative mechanisms involved in the development of NAFLD in the obesity context. A better understanding of the pathophysiological processes underlying NAFLD will allow the development of new therapeutic approaches.
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11
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Sun HJ, Wu ZY, Nie XW, Wang XY, Bian JS. Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential. J Adv Res 2020; 27:127-135. [PMID: 33318872 PMCID: PMC7728580 DOI: 10.1016/j.jare.2020.05.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background Over the last several decades, hydrogen sulfide (H2S) has been found to exert multiple physiological functions in mammal systems. The endogenous production of H2S is primarily mediated by cystathione β-synthase (CBS), cystathione γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are widely expressed in the liver tissues and regulate hepatic functions by acting on various molecular targets. Aim of Review In the present review, we will highlight the recent advancements in the cellular events triggered by H2S under liver diseases. The therapeutic effects of H2S donors on hepatic diseases will also be discussed. Key Scientific Concepts of Review As a critical regulator of liver functions, H2S is critically involved in the etiology of various liver disorders, such as nonalcoholic steatohepatitis (NASH), hepatic fibrosis, hepatic ischemia/reperfusion (IR) injury, and liver cancer. Targeting H2S-producing enzymes may be a promising strategy for managing hepatic disorders.
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Key Words
- 3-MP, 3-mercaptopyruvate
- 3-MST, 3-mercaptopyruvate sulfurtransferase
- AGTR1, angiotensin II type 1 receptor
- AMPK, AMP-activated protein kinase
- Akt, protein kinase B
- CAT, cysteine aminotransferase
- CBS, cystathione β-synthase
- CO, carbon monoxide
- COX-2, cyclooxygenase-2
- CSE, cystathione γ-lyase
- CX3CR1, chemokine CX3C motif receptor 1
- Cancer
- DAO, D-amino acid oxidase
- DATS, Diallyl trisulfide
- EGFR, epidermal growth factor receptor
- ERK, extracellular regulated protein kinases
- FAS, fatty acid synthase
- Fibrosis
- H2S, hydrogen sulfide
- HFD, high fat diet
- HO-1, heme oxygenase 1
- Hydrogen sulfide
- IR, ischemia/reperfusion
- Liver disease
- MMP-2, matrix metalloproteinase 2
- NADH, nicotinamide adenine dinucleotide
- NADPH, nicotinamide adenine dinucleotide phosphate
- NAFLD, non-alcoholic fatty liver diseases
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-kappa B
- NaHS, sodium hydrosulfide
- Nrf2, nuclear factor erythroid2-related factor 2
- PI3K, phosphatidylinositol 3-kinase
- PLP, pyridoxal 5′-phosphate
- PPG, propargylglycine
- PTEN, phosphatase and tensin homolog deleted on chromosome ten
- SAC, S-allyl-cysteine
- SPRC, S-propargyl-cysteine
- STAT3, signal transducer and activator of transcription 3
- Steatosis
- VLDL, very low density lipoprotein
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xin-Yu Wang
- Department of Endocrinology, The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518037, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.,National University of Singapore Research Institute, Suzhou 215000, China
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12
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Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Transl Gastroenterol Hepatol 2020; 5:16. [PMID: 32258520 PMCID: PMC7063528 DOI: 10.21037/tgh.2019.09.08] [Citation(s) in RCA: 322] [Impact Index Per Article: 64.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 09/05/2019] [Indexed: 12/12/2022] Open
Abstract
Liver diseases are fast emerging as global health priorities. Fatty liver is described in the setting of non-alcoholic fatty liver disease (NAFLD) as well as alcoholic liver disease (ALD), the pathogenesis of excess fat being different in the two conditions while both are important components of the changing face of burden of liver diseases worldwide. They are intimately associated with a globalized economy and an increasingly homogenous socio- cultural order with a westernized lifestyle. The accompanying adoption of a progressively sedentary life, consumption of diet dense in calories facilitate development of NAFLD while a spiraling upward trend in alcohol use along with earlier age of drinking as well as increased amount of per capita alcohol consumption increases the prevalence of ALD globally. Adverse health outcomes in NAFLD as well as ALD are caused not only by progressive liver fibrosis that is the most significant factor for liver related and all-cause mortality in both but also by non-liver (cardiovascular, cancer, accidents, neurological) clinical outcomes that calls for a multidisciplinary and social approach to these conditions. We present here an outline of facets of epidemiology of both NAFLD as well as ALD along with its' public health implications. A broad-based integrated approach that incorporates social, behavioral as well as biological targets need to be undertaken at a health system level in a planned manner for these evolving liver health priorities that disproportionately challenges the low- and middle-income countries of Asia, South America and Africa.
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Affiliation(s)
- Souveek Mitra
- Indian Institute of Liver and Digestive Sciences Sitala (east), Jagadishpur, Sonarpur, Kolkata, India
| | - Arka De
- Department of Hepatology, Post Graduate Institute of Medical Education and Research Chandigarh, Chandigarh, India
| | - Abhijit Chowdhury
- Indian Institute of Liver and Digestive Sciences Sitala (east), Jagadishpur, Sonarpur, Kolkata, India
- Department of Hepatology School of Digestive and Liver Diseases Institute of Post Graduate Medical Education & Research Kolkata, India
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13
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Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are two of the most common liver diseases associated with obesity, type 2 diabetes and metabolic syndrome. The prevalence of these conditions are increasingly rising and presently there is not a pharmacological option available in the market. Elucidation of the mechanism of action and the molecular underpinnings behind liver disease could help to better understand the pathophysiology of these illnesses. In this sense, in the last years modulation of the ghrelin system in preclinical animal models emerge as a promising therapeutic tool. In this review, we compile the latest knowledge of the modulation of ghrelin system and its intracellular pathways that regulates lipid metabolism, hepatic inflammation and liver fibrosis. We also describe novel processes implicated in the regulation of liver disease by ghrelin, such as autophagy or dysregulated circadian rhythms. In conclusion, the information displayed in this review support that the ghrelin system could be an appealing strategy for the treatment of liver disease.
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Affiliation(s)
- Mar Quiñones
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
| | - Omar Al-Massadi
- Inserm UMR-S1270, 75005, Paris, France.
- Faculté des Sciences et d'Ingénierie, Sorbonne Université, 75005, Paris, France.
- Institut du Fer a Moulin, Inserm, 17 rue du Fer à Moulin, 75005, Paris, France.
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14
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Seol BG, Kim JH, Woo M, Song YO, Choi YH, Noh JS, Cho EJ. Skate cartilage extracts containing chondroitin sulfate ameliorates hyperlipidemia-induced inflammation and oxidative stress in high cholesterol diet-fed LDL receptor knockout mice in comparison with shark chondroitin sulfate. Nutr Res Pract 2020; 14:175-187. [PMID: 32528626 PMCID: PMC7263899 DOI: 10.4162/nrp.2020.14.3.175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/06/2019] [Accepted: 12/04/2019] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND/OBJECTIVES In this study, we investigated the beneficial effects of skate cartilage extracts containing chondroitin sulfate (SCS) on hyperlipidemia-induced inflammation and oxidative stress in high cholesterol diet (HCD)-fed mice in comparison with the effects of shark cartilage-derived chondroitin sulfate (CS). MATERIALS/METHODS Low-density lipoprotein receptor knockout (LDLR-KO) mice were fed HCD with an oral administration of CS (50 and 100 mg/kg BW/day), SCS (100 and 200 mg/kg BW/day), or water, respectively, for ten weeks. RESULTS The administration of CS or SCS reduced the levels of serum triglyceride (TG), total cholesterol (TC), and LDL cholesterol and elevated the levels of high-density lipoprotein cholesterol, compared with those of the control group (P < 0.05). Furthermore, CS or SCS significantly attenuated inflammation by reducing the serum levels of interleukin (IL)-1β and hepatic protein expression levels of nuclear factor kappa B, inducible nitric oxide synthase, cyclooxygenase-2, and IL-1beta (P < 0.05). In particular, the serum level of tumor necrosis factor-alpha was reduced only in the 100 mg/kg BW/day of SCS-fed group, whereas the IL-6 level was reduced in the 100 and 200 mg/kg BW/day of SCS-fed groups (P < 0.05). In addition, lipid peroxidation and nitric oxide production were attenuated in the livers of the CS and SCS groups mediated by the upregulation of hepatic proteins of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase (P < 0.05). CONCLUSIONS These results suggest that the biological effects of SCS, similar to those of CS, are attributed to improved lipid profiles as well as suppressed inflammation and oxidative stress induced by the intake of HCD.
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Affiliation(s)
- Bo Gyeong Seol
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea
| | - Ji Hyun Kim
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea
| | - Minji Woo
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea.,Busan Innovation Institute of Industry, Science & Technology Planning (BISTEP), Busan 48058, Korea
| | - Yeong Ok Song
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea
| | - Yung Hyun Choi
- Anti-Aging Research Center, Dong-eui University, Busan 47227, Korea.,Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea
| | - Jeong Sook Noh
- Department of Food Science and Nutrition, Tongmyong University, Busan 48520, Korea
| | - Eun Ju Cho
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea
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15
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Moroldo M, Munyaka PM, Lecardonnel J, Lemonnier G, Venturi E, Chevaleyre C, Oswald IP, Estellé J, Rogel-Gaillard C. Integrative analysis of blood and gut microbiota data suggests a non-alcoholic fatty liver disease (NAFLD)-related disorder in French SLA dd minipigs. Sci Rep 2020; 10:234. [PMID: 31937803 PMCID: PMC6959234 DOI: 10.1038/s41598-019-57127-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 12/18/2019] [Indexed: 11/29/2022] Open
Abstract
Minipigs are a group of small-sized swine lines, which show a broad range of phenotype variation and which often tend to be obese. The SLAdd (DD) minipig line was created by the NIH and selected as homozygous at the SLA locus. It was brought to France more than 30 years ago and maintained inbred ever since. In this report, we characterized the physiological status of a herd of French DD pigs by measuring intermediate phenotypes from blood and faeces and by using Large White (LW) pigs as controls. Three datasets were produced, i.e. complete blood counts (CBCs), microarray-based blood transcriptome, and faecal microbiota obtained by 16S rRNA sequencing. CBCs and expression profiles suggested a non-alcoholic fatty liver disease (NAFLD)-related pathology associated to comorbid cardiac diseases. The characterization of 16S sequencing data was less straightforward, suggesting only a potential weak link to obesity. The integration of the datasets identified several fine-scale associations between CBCs, gene expression, and faecal microbiota composition. NAFLD is a common cause of chronic liver disease in Western countries and is linked to obesity, type 2 diabetes mellitus and cardiac pathologies. Here we show that the French DD herd is potentially affected by this syndrome.
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Affiliation(s)
- Marco Moroldo
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France.
| | - Peris Mumbi Munyaka
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
| | - Jérôme Lecardonnel
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | - Gaëtan Lemonnier
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
| | | | | | - Isabelle P Oswald
- Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toxalim, 31027, Toulouse, France
| | - Jordi Estellé
- Université Paris Saclay, INRAE, AgroParisTech, GABI, 78350, Jouy-en-Josas, France
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16
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Nakamura A, Zhu Q, Yokoyama Y, Kitamura N, Uchida S, Kumadaki K, Tsubota K, Watanabe M. Agaricus brasiliensis KA21 May Prevent Diet-Induced Nash Through Its Antioxidant, Anti-Inflammatory, and Anti-Fibrotic Activities in the Liver. Foods 2019; 8:E546. [PMID: 31689883 PMCID: PMC6915480 DOI: 10.3390/foods8110546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/18/2019] [Accepted: 10/28/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a progressive disease that occurs in the liver. As the number of people with NASH has increased, effective prevention and treatment strategies are needed. Agaricus brasiliensis KA21 (AGA) is a mushroom native to Brazil and is considered a healthy food because of its purported health benefits, including its antioxidant properties. In this study, we focused on the oxidative stress that accompanies the onset of NASH and examined whether AGA can prevent NASH development through its antioxidant activity. We used a mouse model of NASH in which pathogenesis was promoted by dietary induction. Supplementation with AGA attenuated the development of hepatic fibrosis, which is a characteristic feature of late-stage NASH. This effect appeared to be mechanistically linked to an AGA-promoted reduction in hepatic oxidative stress. These results demonstrate a novel role for AGA in NASH prevention.
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Affiliation(s)
- Anna Nakamura
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
| | - Qi Zhu
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
- Department of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
| | - Yoko Yokoyama
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
| | - Naho Kitamura
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
| | - Sena Uchida
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
| | - Kayo Kumadaki
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
| | - Kazuo Tsubota
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
- Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.
| | - Mitsuhiro Watanabe
- Systems Biology Program, Graduate School of Media and Governance, Keio University, Kanagawa 252-0882, Japan.
- Health Science Laboratory, Keio Research Institute at SFC, Kanagawa 252-0882, Japan.
- Department of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
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17
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Reliability and Accuracy of Clinical Assessment and Digital Image Analysis for Steatosis Evaluation in Discarded Human Livers. Transplant Proc 2019; 51:1679-1683. [DOI: 10.1016/j.transproceed.2019.04.054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 03/06/2019] [Accepted: 04/22/2019] [Indexed: 12/12/2022]
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18
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Ou Q, Weng Y, Wang S, Zhao Y, Zhang F, Zhou J, Wu X. Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-κB Pathway. Dig Dis Sci 2018; 63:3398-3408. [PMID: 30191499 DOI: 10.1007/s10620-018-5268-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Silybin is the major biologically active compound of silymarin, the standardized extract of the milk thistle (Silybum marianum). Increasing numbers of studies have shown that silybin can improve nonalcoholic steatohepatitis (NASH) in animal models and patients; however, the mechanisms underlying silybin's actions remain unclear. METHODS Male C57BL/6 mice were fed a methionine-choline deficient (MCD) diet for 8 weeks to induce the NASH model, and silybin was orally administered to the NASH mice. The effects of silybin on lipid accumulation, hepatic fibrosis, oxidative stress, inflammation-related gene expression and nuclear factor kappa B (NF-κB) activities were evaluated by biochemical analysis, immunohistochemistry, immunofluorescence, quantitative real-time PCR and western blot. RESULTS Silybin treatment significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NASH mice. Moreover, silybin inhibited HSC activation and hepatic apoptosis and prevented the formation of MDBs in the NASH liver. Additionally, silybin partly reversed the abnormal expression of lipid metabolism-related genes in NASH. Further study showed that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway played important roles in the silybin-derived antioxidant effect, as evidenced by the upregulation of Nrf2 target genes in the silybin treatment group. In addition, silybin significantly downregulated the expression of inflammation-related genes and suppressed the activity of NF-κB signaling. CONCLUSIONS Silybin was effective in preventing the MCD-induced increases in hepatic steatosis, fibrosis and inflammation. The effect was related to alteration of lipid metabolism-related gene expression, activation of the Nrf2 pathway and inhibition of the NF-κB signaling pathway in the NASH liver.
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Affiliation(s)
- Qiang Ou
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China
| | - Yuanyuan Weng
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China
| | - Siwei Wang
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China
| | - Yajuan Zhao
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China
| | - Feng Zhang
- Department of Clinical Laboratory, Core Facility, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.
| | - Jianhua Zhou
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China. .,The Central Laboratory of the Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 201508, China.
| | - Xiaolin Wu
- The Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 200235, China. .,The Central Laboratory of the Eighth People's Hospital of Shanghai, No. 8 Caobao Road, Shanghai, 201508, China.
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19
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Liu T, Wang P, Cong M, Zhao X, Zhang D, Xu H, Liu L, Jia J, You H. Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress. Br J Pharmacol 2018; 175:4480-4495. [PMID: 30266038 DOI: 10.1111/bph.14503] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/23/2018] [Accepted: 09/15/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE Diethyldithiocarbamate (DDC) is a major metabolite of disulfiram that is a potential drug for alcoholism treatment. In the present study, we attempted to explore the possible effect of DDC on non-alcoholic fatty liver disease (NAFLD) and related fibrosis in vivo. EXPERIMENTAL APPROACH C57BL/6 mice and Sprague Dawley (SD) rats received a methionine/choline-deficient (MCD) diet to establish the model of NAFLD with or without DDC treatment. The livers and serum were assessed for histological changes and parameters related to lipid metabolism, liver injury, inflammation and fibrosis. Apoptosis and macrophage related markers were assessed by immunohistochemistry (IHC). KEY RESULTS DDC significantly reduced hepatic steatosis in rats with NAFLD, induced by the MCD diet. DDC reduced the oxidative stress and endoplasmic reticulum stress-related parameters in mice with non-alcoholic steatohepatitis, induced by the MCD diet. IHC for Bax and cleaved caspase-3 showed that DDC inhibited the apoptosis of hepatocytes in the liver. DDC significantly reduced ballooning and Mallory-Denk bodies (MDB) in hepatocytes, accompanied by suppression of serum alanine aminotransferase, aspartate aminotransferase and MDB formation-related genes. DDC significantly alleviated hepatic inflammation, accompanied by suppression of inflammation-related genes. DDC suppressed the infiltration of macrophages, particularly inducible NOS-positive pro-inflammatory macrophages. In addition, DDC significantly alleviated liver fibrosis. Microarray analyses showed that DDC strongly affected lipid metabolism and oxidative stress-related processes and pathways. CONCLUSION AND IMPLICATIONS DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.
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Affiliation(s)
- Tianhui Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hufeng Xu
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lin Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
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20
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Rein-Fischboeck L, Haberl EM, Pohl R, Schmid V, Feder S, Krautbauer S, Liebisch G, Buechler C. Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:526-537. [PMID: 29474931 DOI: 10.1016/j.bbalip.2018.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/23/2018] [Accepted: 02/17/2018] [Indexed: 12/13/2022]
Abstract
Adipose tissue dysfunction contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). The adapter protein alpha-syntrophin (SNTA) is expressed in adipocytes. Knock-down of SNTA increases preadipocyte proliferation and formation of small lipid droplets, which are both characteristics of healthy adipose tissue. To elucidate a potential protective role of SNTA in NASH, SNTA null mice were fed a methionine-choline-deficient (MCD) diet or an atherogenic diet which are widely used as preclinical NASH models. MCD diet mediated loss of fat mass was largely improved in SNTA-/- mice compared to the respective wild type animals. Hepatic lipids were mostly unchanged while the oxidative stress marker malondialdehyde was only induced in the wild type mice. The expression of inflammatory markers and macrophage immigration into the liver were reduced in SNTA-/- animals. This protective function of SNTA loss was absent in atherogenic diet induced NASH. Here, hepatic expression of inflammatory and fibrotic genes was similar in both genotypes though mutant mice gained less body fat during feeding. Hepatic cholesterol and ceramide were strongly induced in both strains upon feeding the atherogenic diet, while hepatic sphingomyelin, phosphatidylserine and phosphatidylethanolamine levels were suppressed. SNTA deficient mice are protected from fat loss and NASH in the experimental MCD model. NASH induced by an atherogenic diet is not influenced by loss of SNTA. The present study suggests the use of different experimental NASH models to study the pathophysiological role of proteins like SNTA in NASH.
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Affiliation(s)
- Lisa Rein-Fischboeck
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Elisabeth M Haberl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Rebekka Pohl
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Verena Schmid
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Susanne Feder
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany
| | - Sabrina Krautbauer
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, Regensburg, Germany.
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21
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Yao X, Xia F, Tang W, Xiao C, Yang M, Zhou B. Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics for the investigation of the effect of Hugan Qingzhi on non-alcoholic fatty liver disease in rats. JOURNAL OF ETHNOPHARMACOLOGY 2018; 212:208-215. [PMID: 29031784 DOI: 10.1016/j.jep.2017.09.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 09/10/2017] [Accepted: 09/15/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hugan Qingzhi tablet (HQT), a traditional Chinese medicine formula has been adopted for preventing and treating nonalcoholic fatty liver disease (NAFLD). AIM In order to explore the anti-NAFLD mechanisms of HQT, iTRAQ-based proteomic was employed to investigate the expression profiles of proteins in NAFLD rats induced by high-fat diet after HQT treatment. MATERIALS AND METHODS The NAFLD rat model was administrated with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, liver histology, pro-inflammatory cytokines, and oxidative stress/antioxidant biomarkers were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the combined strategy of iTRAQ labeling with strong cation exchange-non-liquid chromatography-tandem mass spectrometry (SCX-non-LC-MS/MS) analysis were employed to explore the mechanisms of HQT's protective effect against NAFLD in rats. Western blotting was performed to verify the proteomic results. RESULTS The histopathologic characteristics and biochemical data showed that HQT exhibited protective effects on HFD-induced NAFLD rats. After being analyzed by the combined strategy of iTRAQ with LC-MS/MS and subsequent investigation, we identified 275 differentially expressed proteins in the HFD group, compared to the control; 207 altered proteins in the HQT high dose + HFD group, compared to the HFD group; and 316 altered proteins in the HQT high dose + HFD group, compared to the control. Based on the Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway mapping, the conclusion has reached that several pathways including microbial metabolism in diverse environments, fatty acid metabolism, inflammatory response, oxidative stress, bile secretion, and peroxisome proliferator activated receptor (PPAR) signaling pathway were closely related to the effects of HQT in HFD-induced NAFLD in rats. Furthermore, several differentially expressed proteins, including phytanoyl-CoA 2-hydroxylase (PHYH), acyl-CoA synthetase 1 long chain (ACSL1), hemopexin, Alpha-1-acid glycoprotein (ORM1), fatty acid binding protein 4 (FABP4), soluble sulphotransferase 2a1 (Sult2a1), and argininosuccinate synthase 1 (ASS1) were verified by the western blotting analysis and these results were consistent with the data obtained from the proteomics analysis. CONCLUSIONS Our results not only confirm that Hugan Qingzhi exhibits a significant protective effect in HFD-induced NAFLD rats but also provide a better understanding for the treatments of NAFLD.
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Affiliation(s)
- Xiaorui Yao
- Department of Pharmacy, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou 515041, Guangdong, PR China
| | - Fan Xia
- Department of Pharmacy, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong, PR China
| | - Waijiao Tang
- Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, PR China
| | - Chunxin Xiao
- Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, PR China
| | - Miaoting Yang
- Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, PR China
| | - Benjie Zhou
- Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong, PR China.
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IL-33 treatment attenuated diet-induced hepatic steatosis but aggravated hepatic fibrosis. Oncotarget 2018; 7:33649-61. [PMID: 27172901 PMCID: PMC5085109 DOI: 10.18632/oncotarget.9259] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 04/26/2016] [Indexed: 12/14/2022] Open
Abstract
The aim of our work was to investigate the role of interleukin-33 (IL-33) and its receptor ST2 in the progression of diet-induced nonalcoholic steatohepatitis (NASH) in mice, and the characteristic expression in livers of patients with NASH. Mice were fed with high-fat diet (HFD) or methionine-choline 4-deficient diet (MCD) and injected intraperitoneally with IL-33. Both mRNA and protein expression levels of IL-33 and ST2 were up-regulated in the livers of mice fed with HFD or MCD. Treatment with IL-33 attenuated diet-induced hepatic steatosis and reduced activities of ALT in serum, as well as ameliorated HFD-induced systemic insulin resistance and glucose intolerance, while aggravated hepatic fibrosis in diet-induced NASH. Furthermore, treatment with IL-33 can also promote Th2 response and M2 macrophage activation and beneficial modulation on expression profiles of fatty acid metabolism genes in livers. ST2 deficiency did not affect hepatic steatosis and fibrosis when fed with controlling diet. IL-33 did not affect diet-induced hepatic steatosis and fibrosis in ST2 knockout mice. Meanwhile, in the livers of patients with NASH, IL-33 was mainly located in hepatic sinusoid, endothelial cells, and hepatic stellate cells. The mRNA expression level of IL-33 and ST2 was elevated with the progression of NASH. In conclusion, treatment with IL-33 attenuated diet-induced hepatic steatosis, but aggravated hepatic fibrosis, in a ST2-dependent manner.
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Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort. Sci Rep 2017; 7:17913. [PMID: 29263344 PMCID: PMC5738415 DOI: 10.1038/s41598-017-18076-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/05/2017] [Indexed: 12/15/2022] Open
Abstract
People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.
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Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9:715-732. [PMID: 28652891 PMCID: PMC5468341 DOI: 10.4254/wjh.v9.i16.715] [Citation(s) in RCA: 499] [Impact Index Per Article: 62.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 04/18/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.
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Affiliation(s)
- Mark Benedict
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Xuchen Zhang
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
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The administration of ghrelin improved hepatocellular injury following parenteral feeding in a rat model of short bowel syndrome. Pediatr Surg Int 2016; 32:1165-1171. [PMID: 27651372 DOI: 10.1007/s00383-016-3975-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2016] [Indexed: 12/16/2022]
Abstract
PURPOSE Long-term parenteral nutrition following massive bowel resection causes liver dysfunction, such as intestinal failure-associated liver disease (IFALD). IFALD includes two different states, cholestasis and steatosis, which represents a life-threatening complication. The previous reports have shown the protective role of ghrelin in the liver. The aim of this study was to evaluate the effects of the administration of ghrelin in the liver in a parenterally fed rat model of short bowel syndrome (SBS). METHODS Rats underwent jugular vein catheterization, and were divided into three groups: 90 % small bowel resection (90 % SBR) and TPN (SBS/TPN group), 90 % SBR and TPN plus ghrelin (SBS/TPN/ghrelin group), and sham operation with normal chow (sham group). Ghrelin was administered continuously at a dose of 10 μg/kg/day. On day 13, all rats were euthanized. The serum chemistry was analyzed, the lipid content of the liver was measured, and the liver tissue was histologically analyzed. RESULT The AST and LDH levels significantly increased, and the accumulation of lipids in the liver was observed in the TPN/SBS group. The accumulation of lipids in the liver of the rats in the SBS/TPN group was attenuated by the administration of ghrelin. CONCLUSION The administration of ghrelin has a therapeutic potential for IFALD.
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Regression of fibrosis/cirrhosis by Glycine propionyl-l-carnitine treatment in d-Galactosamine induced chronic liver damage. Chem Biol Interact 2016; 260:117-128. [DOI: 10.1016/j.cbi.2016.11.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 10/05/2016] [Accepted: 11/07/2016] [Indexed: 12/12/2022]
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Genomics of human fatty liver disease reveal mechanistically linked lipid droplet-associated gene regulations in bland steatosis and nonalcoholic steatohepatitis. Transl Res 2016; 177:41-69. [PMID: 27376874 DOI: 10.1016/j.trsl.2016.06.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/13/2016] [Accepted: 06/08/2016] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common disorder hallmarked by excessive lipid deposits. Based on our recent research on lipid droplet (LD) formation in hepatocytes, we investigated LD-associated gene regulations in NAFLD of different grades, that is, steatosis vs steatohepatitis by comparing liver biopsies from healthy controls (N = 13) and NAFLD patients (N = 102). On average, more than 700 differentially expressed genes (DEGs) were identified of which 146 are mechanistically linked to LD formation. We identified 51 LD-associated DEGs frequently regulated in patient samples (range ≥5 to ≤102) with the liver-receptor homolog-1(NR5A2), that is, a key regulator of cholesterol metabolism being commonly repressed among 100 patients examined. With bland steatosis, notable regulations involved hypoxia-inducible lipid droplet-associated-protein and diacylglycerol-O-acyltransferase-2 renowned for their role in LD-growth. Conversely, nonalcoholic steatohepatitis-associated DEGs coded for epidermal growth factor receptor and TLR4 signaling with decreased expression of the GTPase Rab5 and the lipid phosphohydrolase PPAP2B thus highlighting adaptive responses to inflammation, LDL-mediated endocytosis and lipogenesis, respectively. Studies with steatotic primary human hepatocyte cultures demonstrated induction of LD-associated PLIN2, CIDEC, DNAAF1, whereas repressed expression of CPT1A, ANGPTL4, and PKLR informed on burdened mitochondrial metabolism. Equally, repressed expression of the B-lymphocyte chemoattractant CXCL13 and STAT4 as well as induced FGF21 evidenced amelioration of steatosis-related inflammation. In-vitro/in-vivo patient sample comparisons confirmed C-reactive protein, SOCS3, NR5A2, and SOD2 as commonly regulated. Lastly, STRING network analysis highlighted potential "druggable" targets with PLIN2, CIDEC, and hypoxia-inducible lipid droplet-associated-protein being confirmed by immunofluorescence microscopy. In conclusion, steatosis and steatohepatitis specific gene regulations informed on the pathogenesis of NAFLD to broaden the perspective of targeted therapies.
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C-X-C motif chemokine 10 in non-alcoholic steatohepatitis: role as a pro-inflammatory factor and clinical implication. Expert Rev Mol Med 2016; 18:e16. [PMID: 27669973 DOI: 10.1017/erm.2016.16] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD and causes subsequent pathological changes including cirrhosis and hepatocellular carcinoma. Inflammation is the key pathological change in NASH and involves a series of cytokines and chemokines. The C-X-C motif chemokine 10 (CXCL10), which is known as a pro-inflammation chemokine, was recently proven to play a pivotal role in the pathogenesis of NASH. Hepatic CXCL10 is mainly secreted by hepatocytes and liver sinusoidal endothelium. By binding to its specific receptor CXCR3, CXCL10 recruits activated CXCR3+ T lymphocytes and macrophages to parenchyma and promotes inflammation, apoptosis and fibrosis. The circulating CXCL10 level correlates with the severity of lobular inflammation and is an independent risk factor for NASH patients. Thus, CXCL10 may be both a potential prognostic tool and a therapeutic target for the treatment of patients with NASH. The aim of this review is to highlight the growing advances in basic knowledge and clinical interest of CXCL10 in NASH to propagate new insights into novel pharmacotherapeutic avenues.
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30
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Wu W, Patel A, Kyöstilä K, Lohi H, Mladkova N, Kiryluk K, Sun X, Lefkowitch JH, Worman HJ, Gharavi AG. Genome-wide association study in mice identifies loci affecting liver-related phenotypes including Sel1l influencing serum bile acids. Hepatology 2016; 63:1943-56. [PMID: 26857093 DOI: 10.1002/hep.28495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 12/28/2015] [Accepted: 02/04/2016] [Indexed: 01/01/2023]
Abstract
UNLABELLED Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J mice fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and had pleiotropic effects on liver mass, serum cholesterol, and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, sel-1 suppressor of lin-12-like (Sel1l). RNA sequencing and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly down-regulated pathways associated with hepatocyte nuclear factor 1 homeobox A (Hnf1a) and hepatocyte nuclear factor 4A (Hnf4a), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of SEL1L in HepG2 cells resulted in reduced HNF1A and HNF4A and increased bile acids in culture media; it further captured multiple molecular signatures observed in consomic mouse livers with reduced SEL1L. Finally, dogs harboring a SEL1L mutation and Sel1l(+/-) mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism. CONCLUSION Genetic analyses of inbred mouse strains identified loci affecting different liver-related traits and implicated Sel1l as a significant determinant of serum bile acid concentration. (Hepatology 2016;63:1943-1956).
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Affiliation(s)
- Wei Wu
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.,Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Ami Patel
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Kaisa Kyöstilä
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland.,Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.,Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Hannes Lohi
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland.,Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.,Department of Molecular Genetics, Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Nikol Mladkova
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Krzysztof Kiryluk
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Xiaoyun Sun
- JP Sulzberger Columbia Genome Center, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jay H Lefkowitch
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Howard J Worman
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.,Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Ali G Gharavi
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY
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Hayashi A, Shibahara J, Misumi K, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M. Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma. PLoS One 2016; 11:e0155744. [PMID: 27195977 PMCID: PMC4873037 DOI: 10.1371/journal.pone.0155744] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/03/2016] [Indexed: 02/08/2023] Open
Abstract
In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance.
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Affiliation(s)
- Akimasa Hayashi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junji Shibahara
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- * E-mail:
| | - Kento Misumi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Liu W, Baker RD, Bhatia T, Zhu L, Baker SS. Pathogenesis of nonalcoholic steatohepatitis. Cell Mol Life Sci 2016; 73:1969-87. [PMID: 26894897 PMCID: PMC11108381 DOI: 10.1007/s00018-016-2161-x] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/19/2016] [Accepted: 02/09/2016] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease and a risk factor for cirrhosis and hepatocellular carcinoma. The pathological features of NASH include steatosis, hepatocyte injury, inflammation, and various degrees of fibrosis. Steatosis reflects disordered lipid metabolism. Insulin resistance and excessive fatty acid influx to the liver are two important contributing factors. Steatosis is also likely associated with lipotoxicity and cellular stresses such as oxidative stress and endoplasmic reticulum stress, which result in hepatocyte injury. Inflammation and fibrosis are frequently triggered by various signals such as proinflammatory cytokines and chemokines, released by injuried hepatocytes and activated Kupffer cells. Although much progress has been made, the pathogenesis of NASH is not fully elucidated. The purpose of this review is to discuss the current understanding of NASH pathogenesis, mainly focusing on factors contributing to steatosis, hepatocyte injury, inflammation, and fibrosis.
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Affiliation(s)
- Wensheng Liu
- Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA.
| | - Robert D Baker
- Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA
| | - Tavleen Bhatia
- Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA
| | - Lixin Zhu
- Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA
| | - Susan S Baker
- Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children's Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA.
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Yi HW, Ma YX, Wang XN, Wang CF, Lu J, Cao W, Wu XD. Ethanol promotes saturated fatty acid-induced hepatoxicity through endoplasmic reticulum (ER) stress response. Chin J Nat Med 2016; 13:250-6. [PMID: 25908621 DOI: 10.1016/s1875-5364(15)30011-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Indexed: 12/31/2022]
Abstract
Serum palmitic acid (PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes. Ethanol (EtOH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of EtOH on PA-induced lipotoxicity in the liver. Our results indicated that EtOH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. EtOH intensified PA-caused endoplasmic reticulum (ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. EtOH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP(-/-) mice treated with EtOH and high fat diet (HFD), EtOH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of EtOH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing EtOH and saturated fatty acid-induced metabolic complications.
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Affiliation(s)
- Hong-Wei Yi
- Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
| | - Yu-Xiang Ma
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Xiao-Ning Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
| | - Cui-Fen Wang
- Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA
| | - Jian Lu
- Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China
| | - Wei Cao
- Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China
| | - Xu-Dong Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
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Kim DG, Krenz A, Toussaint LE, Maurer KJ, Robinson SA, Yan A, Torres L, Bynoe MS. Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 2016; 13:1. [PMID: 26728181 PMCID: PMC4700622 DOI: 10.1186/s12974-015-0467-5] [Citation(s) in RCA: 189] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 12/23/2015] [Indexed: 12/31/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer’s disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. Methods WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. Results During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. Conclusions Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0467-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Do-Geun Kim
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Antje Krenz
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Leon E Toussaint
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Kirk J Maurer
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. .,Center for Animal Resources and Education, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. .,Center for Comparative Medicine and Research, Dartmouth College, 1 Medical Center Drive, 302 W Borwell, Lebanon, NH 03756, USA.
| | - Sudie-Ann Robinson
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Angela Yan
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Luisa Torres
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
| | - Margaret S Bynoe
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
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Kara M, Dogru T, Genc H, Sertoglu E, Celebi G, Gurel H, Kayadibi H, Cicek AF, Ercin CN, Sonmez A. Neutrophil-to-lymphocyte ratio is not a predictor of liver histology in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2015; 27:1144-1148. [PMID: 26062078 DOI: 10.1097/meg.0000000000000405] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES It has been reported that the neutrophil-to-lymphocyte ratio (NLR) can be measured relatively easily and can serve as a valuable index for much clinical pathology. The aim of this study was to investigate the association between NLR and hepatic histological findings in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND METHODS A total of 226 consecutive patients with biopsy-proven NAFLD [nonalcoholic steatohepatitis (NASH, n=105), borderline-NASH (n=74), and simple steatosis (n=47)] were enrolled. NASH and fibrosis were diagnosed histologically using the NAFLD Clinical Research Network criteria. RESULTS Significant differences were found in aspartate aminotransferase (P<0.001), alanine aminotransferase (P<0.001) levels, and white blood cell (P=0.007) and neutrophil counts (P=0.042) between the three groups of patients. In addition, significantly higher BMI (P=0.024), waist circumference (P=0.011), aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.005), insulin (P=0.008), and homeostasis model assessment-insulin resistance (P=0.009) levels were found in patients with fibrosis (n=133) in comparison with those without fibrosis (n=93). There was no correlation between NLR and glucose, homeostasis model assessment-insulin resistance, lipid parameters, and the NAFLD activity score. Analysis of the NLR in relation to histological findings also showed no association between these parameters. CONCLUSION To the best of our knowledge, this is the largest study that has investigated these relationships in this clinically relevant condition. The findings of the present study show that NLR is not associated with the severity of hepatic inflammation or fibrosis and thus cannot be recommended as a surrogate marker of liver injury in patients with NAFLD.
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Affiliation(s)
- Muammer Kara
- aDepartment of Gastroenterology, GATA Haydarpasa Training Hospital, Istanbul bBiochemistry Laboratory, Ankara Mevki Military Hospital, Anittepe Dispensary Departments of cGastroenterology dPathology eEndocrinology and Metabolism, Gulhane School of Medicine, Ankara fDepartment of Gastroenterology, Izmir Military Hospital, Izmir gBiochemistry Laboratory, Adana Military Hospital, Adana, Turkey
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PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats. Cytokine 2015; 75:127-35. [DOI: 10.1016/j.cyto.2015.05.031] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 04/22/2015] [Accepted: 05/26/2015] [Indexed: 12/12/2022]
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Abstract
There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase.
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Affiliation(s)
- Monjur Ahmed
- Monjur Ahmed, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Ahmed M. Non-alcoholic fatty liver disease in 2015. World J Hepatol 2015; 7:1450-1459. [PMID: 26085906 PMCID: PMC4462685 DOI: 10.4254/wjh.v7.i11.1450] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 04/18/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023] Open
Abstract
There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase.
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Affiliation(s)
- Monjur Ahmed
- Monjur Ahmed, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Hugan Qingzhi Exerts Anti-Inflammatory Effects in a Rat Model of Nonalcoholic Fatty Liver Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:810369. [PMID: 26146507 PMCID: PMC4471380 DOI: 10.1155/2015/810369] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 05/14/2015] [Accepted: 05/18/2015] [Indexed: 12/13/2022]
Abstract
Ethnopharmacological Relevance. The Hugan Qingzhi tablet (HQT) is a traditional Chinese medicine used for treating NAFLD (nonalcoholic fatty liver disease). The present study evaluated the anti-inflammatory effects of HQT in rats with NAFLD. Materials and Methods. HQT was administered daily to the NAFLD experimental groups. Biochemical markers, histopathological data, and oxidative stress/antioxidant biomarkers were determined. Proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were detected by enzyme-linked immunoassay. Expressions of silent information regulator 1 (SIRT1) and acetylated-nuclear-factor kappaB-p65 (Ac-NF-κB-p65) were performed by western blotting. Results. At high and moderate doses, HQT was highly effective in decreasing serum alanine aminotransferase (P < 0.01), aspartate aminotransferase (P < 0.01), hepatic total cholesterol (P < 0.01), triglycerides (P < 0.01), and free fatty acid levels (P < 0.01). Moreover, high and moderate doses of HQT reduced hepatic levels of the proinflammatory cytokines TNF-α (P < 0.01), IL-1β (P < 0.01), and IL-6 (P < 0.01), enhanced SIRT1 expression, and depressed Ac-NF-κB-p65 expression at protein level. Conclusions. In our NAFLD rat model, HQT exerted substantial anti-inflammatory and antioxidant activities, possibly involving the regulation of SIRT1 and Ac-NF-κB-p65 expression.
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Massey VL, Stocke KS, Schmidt RH, Tan M, Ajami N, Neal RE, Petrosino JF, Barve S, Arteel GE. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction. Toxicol Appl Pharmacol 2015; 284:304-14. [PMID: 25759243 PMCID: PMC4515777 DOI: 10.1016/j.taap.2015.02.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/25/2015] [Accepted: 02/26/2015] [Indexed: 12/11/2022]
Abstract
Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9ppm as sodium arsenite) for 10weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects.
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Affiliation(s)
- Veronica L Massey
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Kendall S Stocke
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Robin H Schmidt
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Min Tan
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Nadim Ajami
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Rachel E Neal
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Joseph F Petrosino
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Shirish Barve
- Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Gavin E Arteel
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
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Takagi H, Kobayashi Y, Taguchi O, Takei Y, Sumida Y. Influence of dietary intake of fish oil, magnesium, and zinc on metabolic parameters among individuals tested for diabetes. Nutrition 2015; 31:988-93. [PMID: 26059373 DOI: 10.1016/j.nut.2015.02.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 02/20/2015] [Accepted: 02/28/2015] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The aim of this study was to assess the significance and degree of correlation between the intake of fish oil, magnesium (Mg), and zinc (Zn) and metabolic parameters. METHODS Correlation coefficients among nutrient intake and physical and laboratory parameters were determined using Spearman's rho (ρ) test or a multiple regression model among Japanese individuals (male:female, 37:66; median age, 55 y) who completed a semiquantitative food questionnaire and underwent testing for diabetes. Individuals with diabetes were excluded. RESULTS Spearman's test revealed several weak but significant correlations between intake of fish oil including ω-3 polyunsaturated fatty acids (PUFAs) and various metabolic parameters. The test showed that Zn intake in women significantly correlated with reduced systolic blood pressure (SBP), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GPT), and homeostasis model assessment-insulin resistance (HOMA-IR). Multivariate analysis revealed that intake of fish oil, eicosapentaenoic acid (EPA), and Zn was significantly associated with increased serum levels of high-density lipoprotein cholesterol (HDL-C; fish oil versus HDL-C, P = 0.0438; 95% confidence interval [CI], 0.0055-0.3724; EPA versus HDL-C, P = 0.0439; 95% CI, 0.0053-0.3724; Zn versus HDL-C, P = 0.0041; 95% CI, 0.0890-0.4609). Multivariate analysis revealed that ω-3 PUFAs were associated with decreased serum ALT levels (P = 0.0240; 95% CI, -5.000 to -0.0367) and that Zn correlated with SBP (P = 0.0239; 95% CI, -0.5149 to -0.0377) in women. CONCLUSION Intake of fish oil, Mg, and Zn was associated with some metabolic parameters. Abundant intake of fish oil including ω-3 PUFAs and Zn can exert antiarteriosclerotic effects through increasing serum levels of HDL-C. ω-3 PUFAs can reduce liver inflammation and Zn can reduce SBP in women.
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Affiliation(s)
- Hisayo Takagi
- Faculty of Health Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Yoshinao Kobayashi
- Center for Physical and Mental Health, Mie University Graduate School of Medicine, Tsu, Japan; Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan.
| | - Osamu Taguchi
- Center for Physical and Mental Health, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yasuhiro Sumida
- Center for Physical and Mental Health, Mie University Graduate School of Medicine, Tsu, Japan; Yokkaichi-Hazu Medical Center, Japan Community Healthcare Organization, Yokkaichi, Japan
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Luo Y, Dong X, Yu Y, Sun G, Sun X. Total aralosides of aralia elata (Miq) seem (TASAES) ameliorate nonalcoholic steatohepatitis by modulating IRE1α-mediated JNK and NF-κB pathways in ApoE-/- mice. JOURNAL OF ETHNOPHARMACOLOGY 2015; 163:241-250. [PMID: 25655997 DOI: 10.1016/j.jep.2015.01.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 12/10/2014] [Accepted: 01/15/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Total saponins of Aralia elata (Miq) Seem (TASAES) from the Chinese traditional herb Long ya Aralia chinensis L. is popularly used as a folk medicine to treat rheumatism, neurasthenia, diabetes, hepatitis and antivirus in Asian countries. However, there was poor study of TASAES on Non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory responses and hepatocellular apoptosis exacerbating liver injury. This study aimed to clarify whether or not the anti-inflammatory and anti-apoptotic activities and protective mechanisms of the total aralosides of Aralia elata (Miq) Seem (TASAES) ameliorate NASH in a high-fat diet (HFD)-induced ApoE-/- mouse model. MATERIAL AND METHODS C57/BL6N and ApoE-/- mice were fed with HFD containing 0.3% cholesterol and 20% fat to induce NASH and then treated with TASAES (75,150mg/kg/day, i.g.) for 12 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis. RESULTS ASAES treatment groups exhibited lower serum alanine and aspartate aminotransferases than the NASH group. TASAES could also reduce hepatic steatosis, as revealed by histological changes. In addition, TASAES treatment groups showed lower protein and mRNA expression levels of pro-inflammatory cytokines, such as IL-6, MCP-1, and TNF-α than NASH group. Reduced TUNEL-positive cells were also found in TASAES treatment groups. Western blot and immunohistochemical results indicated that TASAES regulated apoptosis and inflammation-related protein expression. Furthermore, TASAES treatment significantly reduced the phosphorylation of IRE1α, JNK and IκB and the downstream activation of NF-κB p65 was also reduced. CONCLUSION These findings suggested that the ameliorative effects of TASASE in HFD-induced NASH were associated with the regulation of IRE1α-mediated JNK and NF-κB signal pathways, thereby protecting the liver against NASH.
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Affiliation(s)
- Yun Luo
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China
| | - Xi Dong
- Academy of Chinese Materia Medica, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yingli Yu
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China
| | - Guibo Sun
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
| | - Xiaobo Sun
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China.
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Zhang SR, Fan XM. Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21:3214-3222. [PMID: 25805927 PMCID: PMC4363750 DOI: 10.3748/wjg.v21.i11.3214] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 12/29/2014] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
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Wang Y, Jiang ZZ, Chen M, Wu MJ, Guo HL, Sun LX, Wang H, Zhang S, Wang T, Zhang LY. Protective effect of total flavonoid C-glycosides from Abrus mollis extract on lipopolysaccharide-induced lipotoxicity in mice. Chin J Nat Med 2015; 12:461-8. [PMID: 24969528 DOI: 10.1016/s1875-5364(14)60072-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Indexed: 01/16/2023]
Abstract
Abrus mollis is a widely used traditional Chinese medicine for treating acute and chronic hepatitis, steatosis, and fibrosis. It was found that the total flavonoid C-glycosides from Abrus mollis extract (AME) showed potent antioxidant, anti-inflammatory, and hepatoprotective activities. To further investigate the hepatoprotective effect of AME and its possible mechanisms, lipopolysaccharide (LPS)-induced liver injury models were applied in the current study. The results indicated that AME significantly attenuated LPS-induced lipid accumulation in mouse primary hepatocytes as measured by triglyceride (TG) and total cholesterol (TC) assays and Oil Red O staining. Meanwhile, AME exerted a protective effect on LPS-induced liver injury as shown by decreased liver index, serum aminotransferase levels, and hepatic lipid accumulation. Real-time PCR and immunoblot data suggested that AME reversed the LPS-mediated lipid metabolism gene expression, such as sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase 1 (ACC1). In addition, LPS-induced overexpression of activating transcription factor 4 (ATF4), X-box-binding protein-1 (XBP-1), and C/EBP homologous protein (CHOP) were dramatically reversed by AME. Furthermore, AME also decreased the expression of LPS-enhanced interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Here, it is demonstrated for the first time that AME ameliorated LPS-induced hepatic lipid accumulation and that this effect of AME can be attributed to its modulation of hepatic de novo fatty acid synthesis. This study also suggested that the hepatoprotective effect of AME may be related to its down-regulation of unfolded protein response (UPR) activation.
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Affiliation(s)
- Yun Wang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zhen-Zhou Jiang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China
| | - Mi Chen
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Mei-Juan Wu
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Hong-Li Guo
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Li-Xin Sun
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Hao Wang
- Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Shuang Zhang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Tao Wang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 21009, China
| | - Lu-Yong Zhang
- Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
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Tzeng TF, Liou SS, Chang CJ, Liu IM. 6-gingerol protects against nutritional steatohepatitis by regulating key genes related to inflammation and lipid metabolism. Nutrients 2015; 7:999-1020. [PMID: 25658238 PMCID: PMC4344571 DOI: 10.3390/nu7020999] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 12/26/2014] [Accepted: 01/16/2015] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis (NASH), appears to be increasingly common worldwide. The aim of the study was to investigate the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone), a bioactive ingredient of plants belonging to the Zingiberaceae family, on experimental models of NASH. In HepG2 cells, 6-gingerol (100 μmol/L) treatment inhibited free fatty acids mixture (0.33 mmol/L palmitate and 0.66 mmol/L oleate)-induced triglyceride and inflammatory marker accumulations. Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After four weeks of MCD diet feeding, the mice were dosed orally with 6-gingerol (25, 50 or 100 mg/kg/day) once daily for another four weeks. 6-Gingerol (100 mg/kg/day) attenuated liver steatosis and necro-inflammation in MCD diet-fed mice. The expressions of inflammatory cytokine genes, including those for monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6, and nuclear transcription factor (NF-κB), which were increased in the livers of MCD diet-fed mice, were attenuated by 6-gingerol. 6-Gingerol possesses a repressive property on hepatic steatosis, which is associated with induction of peroxisome proliferator-activated receptor α. Our study demonstrated the protective role of 6-gingerol in ameliorating nutritional steatohepatitis. The effect was mediated through regulating key genes related to lipid metabolism and inflammation.
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Affiliation(s)
- Thing-Fong Tzeng
- Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Tajen University, Yanpu Township, 90741 Pingtung County, Taiwan.
| | - Shorong-Shii Liou
- Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Tajen University, Yanpu Township, 90741 Pingtung County, Taiwan.
| | - Chia Ju Chang
- Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Tajen University, Yanpu Township, 90741 Pingtung County, Taiwan.
| | - I-Min Liu
- Department of Pharmacy & Graduate Institute of Pharmaceutical Technology, Tajen University, Yanpu Township, 90741 Pingtung County, Taiwan.
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Doganay L, Katrinli S, Colak Y, Senates E, Zemheri E, Ozturk O, Enc FY, Tuncer I, Doganay GD. HLA DQB1 alleles are related with nonalcoholic fatty liver disease. Mol Biol Rep 2014; 41:7937-7943. [PMID: 25156535 DOI: 10.1007/s11033-014-3688-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 08/20/2014] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD is a complex disease and inflammation is a crucial component in the disease pathogenesis. Recent genome wide association studies in hepatology area highlighted significant relations with human leukocyte antigen (HLA) DQ region and certain liver diseases. The previous animal models also emphasized the involvement of adaptive immune system in the liver damage pathways. To investigate possible polymorphisms in the HLA region that can contribute to the immune response affecting the NAFLD, we enrolled 93 consecutive biopsy proven NAFLD patients and a control group consisted of 101 healthy people and genotyped HLA DQB1 alleles at high resolution by sequence specific primers-polymerase chain reaction. The mean NAFLD activity score (NAS) was 5.2 ± 1.2, fibrosis score was 0.9 ± 0.9, ALT was 77 ± 47.4 U/L, AST was 49.4 ± 26.3 U/L. Among 13 HLA DQB1 alleles analyzed in this study, DQB1*06:04 was observed significantly at a more frequent rate among the NAFLD patients compared to that of healthy controls (12.9 vs. 2 % χ(2) = 8.6, P = 0.003, P c = 0.039, OR: 7.3 95 % CI 1.6-33.7). In addition, the frequency of DQB1*03:02 was significantly higher in the healthy control group than the NAFLD patients (24.8 vs. 7.5 %, χ(2) = 10.4, P = 0.001, P c = 0.013, OR: 0.2, 95 % CI 0.1-0.6). NAFLD patients were grouped according to their fibrosis score and NAS. The distribution of DQB1 alleles over stratified NAFLD patients did not reveal any statistically significant relation. Taken together, immune repertoire of individuals may have an effect on NAFLD pathogenesis and therefore, in NAFLD, adaptive immunity pathways should be investigated.
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Affiliation(s)
- Levent Doganay
- Department of Gastroenterology, Goztepe Teaching and Research Hospital, Medeniyet University, Istanbul, Turkey,
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Transcriptome analysis on the inflammatory cell infiltration of nonalcoholic steatohepatitis in bama minipigs induced by a long-term high-fat, high-sucrose diet. PLoS One 2014; 9:e113724. [PMID: 25415189 PMCID: PMC4240652 DOI: 10.1371/journal.pone.0113724] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 10/28/2014] [Indexed: 01/07/2023] Open
Abstract
Long-term adherence to a high-fat, high-calorie diet influences human health and causes obesity, metabolic syndrome and nonalcoholic steatohepatitis (NASH). Inflammation plays a key role in the development of NASH; however, the mechanism of inflammation induced by over-nutrition remains largely unknown. In this study, we fed Bama minipigs a high-fat, high-sucrose diet (HFHSD) for 23 months. The pigs exhibited characteristics of metabolic syndrome and developed steatohepatitis with greatly increased numbers of inflammatory cells, such as lymphocytes (2.27-fold, P<0.05), Kupffer cells (2.59-fold, P<0.05), eosinophils (1.42-fold, P<0.05) and neutrophils (2.77-fold, P<0.05). High-throughput RNA sequencing (RNA-seq) was performed to explore the systemic transcriptome of the pig liver during inflammation. Approximately 18.2 gigabases of raw sequence data were generated, and over 303 million high-quality reads were assembled into 21,126 unigenes. RNA-seq data analysis showed that 822 genes were differentially expressed in liver (P<0.05) between the HFHSD and control groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the process of inflammation involved the inflammatory signal transduction-related toll-like receptor, MAPK, and PPAR signaling pathways; the cytokine-related chemokine signaling, cytokine-cytokine receptor interaction, and IL2, IL4, IL6, and IL12 signaling pathways; the leukocyte receptor signaling-related T cell, B cell, and natural killer cell signaling pathways; inflammatory cell migration and invasion- related pathways; and other pathways. Moreover, we identified several differentially expressed inflammation-related genes between the two groups, including FOS, JUN, TLR7, MYC, PIK3CD, VAV3, IL2RB and IL4R, that could be potential targets for further investigation. Our study suggested that long-term HFHSD induced obesity and liver inflammation, providing basic insight into the molecular mechanism of this condition and laying the groundwork for further studies on obesity and steatohepatitis.
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Xin HG, Zhang BB, Wu ZQ, Hang XF, Xu WS, Ni W, Zhang RQ, Miao XH. Treatment with baicalein attenuates methionine−choline deficient diet-induced non-alcoholic steatohepatitis in rats. Eur J Pharmacol 2014; 738:310-8. [DOI: 10.1016/j.ejphar.2014.06.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 06/03/2014] [Accepted: 06/06/2014] [Indexed: 02/07/2023]
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Liang W, Lindeman JH, Menke AL, Koonen DP, Morrison M, Havekes LM, van den Hoek AM, Kleemann R. Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation. J Transl Med 2014; 94:491-502. [PMID: 24566933 DOI: 10.1038/labinvest.2014.11] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 01/17/2014] [Accepted: 01/27/2014] [Indexed: 02/06/2023] Open
Abstract
The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components (neutrophils, AP-1 pathway) and causes NASH.
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Affiliation(s)
- Wen Liang
- 1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Departments of Endocrinology and Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan H Lindeman
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Debby P Koonen
- Department of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Martine Morrison
- The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands
| | - Louis M Havekes
- 1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Departments of Endocrinology and Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Anita M van den Hoek
- The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands
| | - Robert Kleemann
- 1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
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