Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice
| Autor: | Brent A. Neuschwander-Tetri, David G. Parkes, Peter S. Griffin, James Napora, Carrie S. Dolman, Elizabeth M. Brunt, Jonathan D. Roth, Mary Erickson, James L. Trevaskis, Carrie Wittmer |
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| Rok vydání: | 2012 |
| Předmět: |
Leptin
Male Nonalcoholic steatohepatitis medicine.medical_specialty Endpoint Determination Physiology Gene Expression Mice Obese Biology Diet High-Fat Glucagon-Like Peptide-1 Receptor Mice Liver Function Tests Non-alcoholic Fatty Liver Disease Fibrosis Physiology (medical) Internal medicine Weight Loss Receptors Glucagon medicine Animals Receptor Diet Fat-Restricted Mice Knockout Hepatology medicine.diagnostic_test Body Weight Gastroenterology Trans Fatty Acids medicine.disease Lipids Glucagon-like peptide-1 Hormones Diet Fatty Liver Mice Inbred C57BL Endocrinology Liver metabolism Liver Body Composition Steatosis Peptides Liver function tests Exenatide hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 302:G762-G772 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00476.2011 |
| Popis: | These preclinical studies aimed to 1) increase our understanding the dietary induction of nonalcoholic steatohepatitis (NASH), and, 2) further explore the utility and mechanisms of glucagon-like peptide-1 receptor (GLP-1R) agonism in NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of nonalcoholic fatty liver disease (NAFLD)/NASH in Lepob/Lepoband C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lepob/Lepoband B6 ameliorated hepatic endpoints in both dietary models. Next, we assessed whether AC3174-mediated improvements in diet-induced NASH were solely due to weight loss in HTF-fed mice. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma alanine aminotransferase, and triglycerides, whereas a calorie-restricted, weight-matched group demonstrated only modest nonsignificant 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-1Rs in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support the clinical evaluation of the utility of GLP-1R agonists for treatment of NASH. |
| Databáze: | OpenAIRE |
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