Hepatoprotective Effects of MHY3200 on High-Fat, Diet-Induced, Non-Alcoholic Fatty Liver Disease in Rats

This study investigated the effects of 2-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2,2-difluoroacetic acid (MHY3200) on high-fat diet (HFD)-induced hepatic lipid accumulation and inflammation. The measurement of peroxisome proliferator-activated receptor (PPAR) activity by using a luciferase assay indicated that MHY3200 was more potent than a known PPAR agonist, WY14643, in AC2F cells. Six-month-old male SD rats were fed chow or HFD for 1 month, and after, with or without added MHY3200 (1 or 2 mg/kg/day) for 4 weeks. The oral administration of MHY3200 caused a significant decrease in serum triglyceride (TG), glucose, alanine aminotransferase, and insulin, as well as a slight decrease in the level of free fatty acid and aspartate transaminase. No weight gain was detected when compared with HFD rats, and hepatic TG content was also attenuated by the administration of MHY3200. Furthermore, phosphorylation of the ER stress marker, inositol-requiring kinase 1 and its downstream gene, c-Jun N-terminal kinase, in addition to serine phosphorylation of insulin receptor substrate 1 were suppressed by MHY3200. Consistent with these results, MHY3200 administration reduced the levels of activation of protein-1, cyclooxygenase-2, and inducible nitric oxide synthase. Our results suggested that MHY3200 ameliorated HFD-induced hepatic lipid accumulation and inflammation, and improved insulin resistance through PPAR activation.