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Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice.
Am J Physiol Gastrointest Liver Physiol. 2012 Apr 15; 302(8):G762-72.AJ

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+Show Affiliations

Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22268099

Citation

Trevaskis, James L., et al. "Glucagon-like Peptide-1 Receptor Agonism Improves Metabolic, Biochemical, and Histopathological Indices of Nonalcoholic Steatohepatitis in Mice." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 302, no. 8, 2012, pp. G762-72.
Trevaskis JL, Griffin PS, Wittmer C, et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2012;302(8):G762-72.
Trevaskis, J. L., Griffin, P. S., Wittmer, C., Neuschwander-Tetri, B. A., Brunt, E. M., Dolman, C. S., Erickson, M. R., Napora, J., Parkes, D. G., & Roth, J. D. (2012). Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. American Journal of Physiology. Gastrointestinal and Liver Physiology, 302(8), G762-72. https://doi.org/10.1152/ajpgi.00476.2011
Trevaskis JL, et al. Glucagon-like Peptide-1 Receptor Agonism Improves Metabolic, Biochemical, and Histopathological Indices of Nonalcoholic Steatohepatitis in Mice. Am J Physiol Gastrointest Liver Physiol. 2012 Apr 15;302(8):G762-72. PubMed PMID: 22268099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. AU - Trevaskis,James L, AU - Griffin,Peter S, AU - Wittmer,Carrie, AU - Neuschwander-Tetri,Brent A, AU - Brunt,Elizabeth M, AU - Dolman,Carrie S, AU - Erickson,Mary R, AU - Napora,James, AU - Parkes,David G, AU - Roth,Jonathan D, Y1 - 2012/01/19/ PY - 2012/1/24/entrez PY - 2012/1/24/pubmed PY - 2012/5/30/medline SP - G762 EP - 72 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 302 IS - 8 N2 - 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. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/22268099/Glucagon_like_peptide_1_receptor_agonism_improves_metabolic_biochemical_and_histopathological_indices_of_nonalcoholic_steatohepatitis_in_mice_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00476.2011?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -