title: Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.
abstract: 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 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 pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lep(ob)/Lep(ob) and 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.
authors.affiliation: Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Trevaskis
authors.forename: Peter S
authors.initials: PS
authors.lastname: Griffin
authors.forename: Carrie
authors.initials: C
authors.lastname: Wittmer
authors.forename: Brent A
authors.initials: BA
authors.lastname: Neuschwander-Tetri
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Carrie S
authors.initials: CS
authors.lastname: Dolman
authors.forename: Mary R
authors.initials: MR
authors.lastname: Erickson
authors.forename: James
authors.initials: J
authors.lastname: Napora
authors.forename: David G
authors.initials: DG
authors.lastname: Parkes
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Roth
mesh_terms: D000818:Animals; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D023381:Endpoint Determination; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D006728:Hormones / Q000097:blood; D020738:Leptin / Q000235:genetics; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D010455:Peptides / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics; D044242:Trans Fatty Acids / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: C553564:AC3174; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D006728:Hormones; D020738:Leptin; D008055:Lipids; D010455:Peptides; D018027:Receptors, Glucagon; D044242:Trans Fatty Acids