Endocrine Abstracts

Objective: Non-alcoholic fatty liver disease (NAFLD) is a progressive disease caused by a build-up of fat in the liver and onsets with simple steatosis, potentially advancing to non-alcoholic steatohepatitis (NASH) in the presence of inflammation and fibrosis, severely leading to cirrhosis or hepatocellular carcinoma. There is increasing cumulative evidence indicating that sodium-glucose cotransport 2 (SGLT2) inhibitor agents efficaciously alleviate NASH in a novel mouse model, but there is no study mentioning the effect of Enavogliflozin on liver disease. Consequently, in this present study, we investigated the impact of this sodium-glucose cotransport 2 inhibitor on high-fat high-cholesterol diet (HFHCD)-induced NASH mice. Methods Male C57BL/6 mice were fed a chow diet, HFHCD, or HFHCD with Enavogliflozin for 12 weeks. Enavogliflozin was administered at a dose of 1.28 mg/kg/day in these experiments. In vitro, human hepatic stellate cells (LX-2 cells) were treated with transforming growth factor beta 1 (TGF-β1) in the presence or absence of Enavogliflozin.

Results: HFHCD induced excessive hepatic lipid accumulation, immune cell infiltration, and severe fibrosis. Enavogliflozin administration not only ameliorated hepatic steatosis and fibrotic condition but also suppressed the production of inflammatory cytokines (IL-6, IL-1β). In the in vitro study, in addition to decreasing SGLT2 expression induced by TGF-β1, enavogliflozin inhibited hepatic stellate cell activation by reducing proliferation, wound healing migration, and suppressing the expression of αSMA.

Conclusion: Our results suggest that enavogliflozin shows efficacy in a mouse model of NASH and liver fibrosis by attenuating hepatic steatosis, suppressing inflammation, and inhibiting hepatic stellate cell activation in vitro.