PPARγ-dependent and -independent regulation of genes involved in hepatic methionine cycle in fasted or diet-induced obese mice

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with increased expression of hepatocyte peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and reduced expression of hepatic genes involved in the methionine cycle. The nuclear receptor PPARγ is activated by fatty acids, and we have shown that the knockout of Pparg in hepatocytes (PpargΔHep) reduces the negative effects of MASH on the metabolism of methionine. Here, we sought to determine whether hepatocyte Pparg is required for the transcriptional regulation of genes involved in the methionine cycle in conditions with altered fatty acid flux to the liver: fasting, refeeding, and high-fat diet (HFD)-induced obesity/steatosis. Fasting increased the expression of key genes involved in the methionine cycle, whereas 6h-refeeding reversed these effects and reduced the expression of phosphatidylethanolamine N-methyltransferase (Pemt) and cystathionine beta synthase (Cbs). Although fasting increased hepatocyte Pparg expression, PpargΔHep did not enhance the fasting and refeeding-mediated regulation of methionine cycle gene expression. We previously reported that diet-induced steatosis increased hepatocyte Pparg expression, and here we show that PPARγ-specific agonist rosiglitazone (RSG) reduced the expression of betaine homocysteine S-methyltransferase (Bhmt) and Cbs in diet-induced obese control mice. The PPARγ-dependent reduction of hepatic Bhmt and Cbs expression was confirmed in mouse primary hepatocytes. Interestingly, PpargΔHep increased the expression of Pemt in HFD-fed mice and that of key genes of the methionine cycle in RSG-treated obese mice, including Pemt, Bhmt and Cbs, suggesting that Pparg negatively regulates their expression in the liver.