| Glucagon-like peptide-1 (GLP-1) receptor agonism improves metabolic, biochemical and histopathological indices of nonalcoholic steatohepatitis (NASH) in mice. | |
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MedLine Citation:
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PMID: 22268099 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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These preclinical studies aimed to (1) increase our understanding the dietary induction of NASH, and, (2) further explore the utility and mechanisms of GLP-1 receptor (GLP-1R) agonism in treating NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of NAFLD/NASH in Lep(ob)/Lep(ob) and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiologic features of NASH (e.g., hepatic steatosis and fibrosis). Administration of AC3174, an exenatide analog and GLP-1R agonist, to Lep(ob)/Lep(ob) and B6 mice attenuated hepatic endpointsin both dietary models. Next, we assessed whether AC3174-mediated improvements in HTF diet-induced NASH were solely due to weight loss. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma ALT and triglycerides, whereas a calorie-restricted weight-matched group demonstrated only modest non-significant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1R's in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support clinical evaluation of the utility of GLP-1R agonists for treatment of NASH. |
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Authors:
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James L Trevaskis; Peter S Griffin; Carrie Wittmer; Brent A Neuschwander-Tetri; Elizabeth M Brunt; Carrie S Dolman; Mary R Erickson; James Napora; David G Parkes; Jonathan David Roth |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-19 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: - ISSN: 1522-1547 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Novartis Institutes for BioMedical Research. |
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