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

Abstract

Background & AimsNon-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) in humans. Although we previously showed that the expression of PPAR{gamma} in hepatocytes contributes to the development NASH in lean mice, the relevance of hepatocyte PPAR{gamma} in the development of NASH associated with obesity is still poorly understood. MethodsHepatocyte PPAR{gamma} was knocked out (Pparg{Delta}Hep) after the development of high-fat diet-induced obesity in male and female mice and before NASH was induced with a high fat, cholesterol and fructose (HFCF) diet. We assessed the effect of the diets and Pparg{Delta}Hep on body composition and glucose homeostasis, as well as on the liver pathology, gene expression, and metabolome. In addition, liver biopsies from a cohort of 102 bariatric surgery patients were assessed for liver histology and gene expression. ResultsPPAR{gamma} expression, specifically PPAR{gamma}2, is mostly derived from hepatocytes and increased by high fat diets. Pparg{Delta}Hep reduced HFCF-induced NASH progression without altering steatosis. Interestingly, Pparg{Delta}Hep reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and collagen- stained fibrotic area in the liver of HFCF-fed male mice. In addition, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPAR{gamma}-dependent manner. Specifically, Pparg{Delta}Hep increased betaine-homocysteine methyltransferase expression and reduced homocysteine levels in HFCF- fed male mice. In a cohort of 102 bariatric surgery patients, 16 cases of NASH were associated with increased insulin resistance and hepatic PPAR{gamma} expression. ConclusionsHepatocyte PPAR{gamma} expression associated with obesity could regulate methionine metabolism and the progression of fibrosis in NASH.