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 γ (PPARγ) in humans. Although we previously showed that the expression of PPARγ in hepatocytes contributes to the development NASH in lean mice, the relevance of hepatocyte PPARγ in the development of NASH associated with obesity is still poorly understood.MethodsHepatocyte PPARγ was knocked out (PpargΔHep) 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 PpargΔHep 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.ResultsPPARγ expression, specifically PPARγ2, is mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis. Interestingly, PpargΔHep 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 PPARγ-dependent manner. Specifically, PpargΔHep 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 PPARγ expression.ConclusionsHepatocyte PPARγ expression associated with obesity could regulate methionine metabolism and the progression of fibrosis in NASH.