Endocrine Abstracts

Although non-alcoholic fatty liver disease (NAFLD) patients are rapidly growing, there is not optimal therapy to improve NAFLD. NAFLD is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activator thiazolidinediones (TZD) is an insulin sensitizer, and have been focused as the drug for NAFLD. However, the TZD remain debate as drug of choice on NAFLD because of its conflicting results on the hepatic steatosis and fibrosis. Lobeglitazone could be more potent effects for improving insulin sensitivity in the T2DM patients. In the present study, we investigated the effects of new developed TZD, lobeglitazone on animal model with obesity-associated hepatic steatohepatitis, focusing on the lipid metabolism in liver. Lobeglitazone treatment for 4 weeks in high fat diet (HFD)-induced obese mice (HL group) improved the insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene related to hepatic gluconeogenesis also decreased by treatment of lobeglitazone. The liver of mice in HL group showed histologically reduced lipid accumulation with the lower plasma total cholesterol and triglyceride level. In addition, the HL group induced the significant decreases in the hepatic transcription levels of hepatic lipid synthesis, cholesterol biosynthesis and lipid droplet development genes, and the increase in the gene expressions of fatty acid β-oxidation. It suggested that lobeglitazone ameliorated the hepatic steatosis and recovered the hepatic lipid dysregulation. Liver with steatohepatitis increased not only the PPARγ, but also the phosphorylation of PPARγ at serine 273 (pS273) that leads to down-regulation of gene expression linked in insulin sensitivity. Lobeglitazone interestingly diminished the pS273 of PPARγ. It suggested that post-translational modification of PPARγ in liver by lobeglitazone might be one of underlying mechanisms for improvement of NAFLD. Collectively, lobeglitazone had potent beneficial effects on insulin sensitivity and hepatic steatosis through improvement of hepatic lipid metabolism. Our data revealed that the lobeglitazone shed the light on the novel therapy for the NAFLD.