A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice

Abstract

Since non-alcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the eff ects of G49, a dual glucagon-like peptide-1(GLP-1)/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or methionine/choline-defi cient diet for one week were divided into 4 groups: chow diet, MCD, MCD diet, chow diet plus G49 and MCD diet plus G49. Mice fed high fat diet (HFD) for 10 weeks were divided in groups: HFD and HFD plus G49. Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy was performed and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration and comprehensive genomic and metabolic profi ling was conducted. NASH was ameliorated in M+G49 group manifested by reduced infl ammation, steatosis, oxidative stress, apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose utilization via pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored cytokine-mediated priming phase and enhanced proliferative capacity and hepatic regeneration ratio in mice on MCD diet. NASH markers remained decreased in M+G49 mice after PH and glucose utilization was shifted to PPC and oxidative metabolism. G49 administered immediately after PH was also eff ective in alleviating the pathological changes induced by the MCD diet. Benefi ts on liver regeneration were also found in mice fed HFD treated with G49. In conclusion, dual acting GLP-1R/GCGR agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly in those requiring PH.