PPARγ-dependent and -independent regulation of methionine metabolism by diet-induced obesity and fasting in male mice

Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is associated with increased expression of peroxisome proliferator-activated receptor gamma (PPARγ, Pparg ) and reduced expression of genes involved in methionine metabolism in the liver. The nuclear receptor PPARγ is activated by fatty acids, and the knockout of Pparg in hepatocytes ( Pparg ΔHep ) reduced the negative effects of MASH on methionine metabolism. Here, we sought to determine whether hepatocyte Pparg is required for the transcriptional regulation of genes involved in hepatic methionine metabolism in conditions with altered fatty acid flux to the liver: fasting, refeeding, and high-fat diet (HFD)-induced obesity/steatosis. Fasting induced liver steatosis and increased the expression of key genes involved in the methionine metabolism in the liver, while 6h-refeeding reversed these effects and reduced the expression of phosphatidylethanolamine N-methyltransferase ( Pemt) and cystathionine beta synthase ( Cbs) . Overall, fasting and refeeding did not alter hepatocyte Pparg expression nor Pparg ΔHep affected fasting and refeeding-mediated regulation of methionine metabolism gene expression. Diet-induced steatosis reduced hepatic Pemt expression in control ( Pparg -intact) mice, and the thiazolidinedione (TZD)-mediated activation of PPARγ in diet-induced obese control ( Pparg -intact) mice reduced the expression of betaine homocysteine S-methyltransferase ( Bhmt) and Cbs . However, diet-induced steatosis increased hepatocyte Pparg expression, and Pparg ΔHep blocked the negative effects of HFD and TZD on hepatic methionine metabolism. The PPARγ-dependent reduction of hepatic Bhmt and Cbs expression was confirmed in mouse primary hepatocytes. Taken together, hepatocyte Pparg may serve as a negative regulator of hepatic methionine metabolism in diet-induced obese mice and these actions could contribute to promoting the onset of MASH.