The use of CHS-131, a selective PPAR-gamma modulator to treat NAFLD/NASH
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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) is a spectrum of diseases that is rising in prevalence and is strongly associated with obesity, diabetes, and insulin resistance. There has been much research into potential therapeutics, as the current recommended treatment, thiazolidinediones (TZDs) present a host of negative side effects such as fluid retention and weight gain. CHS-131 is a selective PPAR-γ modulator with antidiabetic effects and less side effects compared to TZDs. The aim of this study was to investigate the effects of CHS-131 on metabolic parameters and liver pathology in a diet-induced obese (DIO) and biopsy-confirmed mouse model of non-alcoholic steatohepatitis. METHODS: Male C57BL/6JRj mice were fed an AMLN diet (40% fat with trans-fat, 20% fructose and 2% cholesterol) for 33 weeks prior to a liver biopsy procedure. Animals that were biopsy-confirmed to have steatosis and fibrosis were stratified into 3 treatment groups: 1) Low dose CHS-131 (10mg/kg), 2) High dose CHS-131 (30mg/kg), 3) Vehicle. Metabolic parameters, liver pathology including NAFLD activity score, metabolomics/lipidomics, markers of liver function and liver, subcutaneous and visceral adipose tissue gene expression was assessed. RESULTS: CHS-131 did not affect body weight, fat, lean or water mass, or food intake in DIO-NASH mice with fibrosis. CHS-131 improved fasting insulin levels and insulin sensitivity as assessed by intraperitoneal insulin tolerance test. CHS-131 improved total cholesterol, ALT, AST and increased adiponectin levels in plasma. CHS-131 improved NAS in liver histology and tended to reduce markers of hepatic fibrosis. Diet induced NASH mice treated with CHS-131 demonstrated a hepatic shift to diacyl- and triacyl-glycerol’s with shorter chains, increased expression of genes stimulating fatty acid oxidation and browning and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis and inflammation in adipose tissue. CONCLUSION: CHS-131 improves liver histology in a diet-induced obese and biopsy confirmed mouse model of NASH by affecting the hepatic lipidome, reducing insulin resistance and altering lipid metabolism and inflammation in adipose tissue.