Exenatide Treatment Improves Mitochondrial Metabolism and Hepatic Insulin Sensitivity in Mice with Nonalcoholic Steatohepatitis (NASH)

Abstract

Exenatide (Exe) is a glucagon-like peptide-1agonist (GLP-1) that enhances insulin production, slows gastric emptying and reduces appetite. Nonalcoholic fatty liver disease (NAFLD), and its more severe form known as NASH, are frequent complications of T2DM. As mitochondrial dysfunction and lipotoxicity are central features of NASH, we tested whether Exe improved mitochondrial oxidative function and hepatic insulin resistance in this setting. Mice (C57/BL6) were fed either a high-fructose, high trans-fat (TFD) diet for 24 weeks to induce NASH or a control diet. After 16 weeks, mice were randomly assigned for the final 8 weeks to subcutaneous Exe (30 µg/kg/day) or vehicle. After an overnight fast, mice received an i.v. infusion of [13C3] propionate and [3,4-13C2] glucose to evaluate mitochondrial metabolism by NMR-based 13C-isotopomer analysis. Targeted metabolic analysis of lipids was measured by LC-MS/MS. Exenatide reduced liver weight and intrahepatic triglyceride content (TFD: 287±23 vs. Exe: 198±27 mg/g liver, p=0.03). Fasting plasma glucose, insulin, FFA and TGs were all significantly lower with Exe. Expression of lipogenic genes and inflammatory markers were significantly lowered by Exe. Moreover, Exe reduced hepatic glucose production, TCA cycle flux, anaplerosis and pyruvate cycling. Exenatide administration improved the lipidomic profile, and decreased hepatic byproducts resulting from incomplete fat oxidation (typically associated with insulin resistance/lipotoxicity), such as diacylglycerols (TFD: 111±13 vs. Exe: 64±13 µmol/g protein, p=0.02) and ceramides (TFD: 1.6±0.1 vs. Exe: 1.3±0.1 µmol/g protein, p=0.02). Conclusion: In an animal model of NASH, Exe improves hepatic insulin sensitivity, mitochondrial TCA cycle flux and reduces toxic lipid metabolites resulting in an improvement of mitochondrial function. Taken together, these results suggest that Exe may be of clinical value in the management of NASH. Disclosure S. Kalavalapalli: None. F. Bril: None. A. Vergara: None. N. Sunny: None. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..