Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor gamma (PPAR gamma). However, the relevance of hepatocyte PPAR gamma in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPAR gamma was knocked out (Pparg(delta Hep)) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPAR gamma expression was mostly derived from hepatocytes and increased by high fat diets. Pparg(delta Hep) reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPAR gamma-dependent manner. Pparg(delta Hep) increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPAR gamma expression. Our study shows that hepatocyte PPAR gamma expression is associated with NASH in mice and humans. In male mice, hepatocyte PPAR gamma negatively regulates methionine metabolism and contributes to the progression of fibrosis.