Sex- and hepatocyte PPARγ-dependent effects of an obesogenic dietary approach to induce MASH with fibrosis in mice

Mouse models of metabolic dysfunction-associated steatotic liver disease (MASLD) are valuable tools for identifying novel molecular mechanisms that drive progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH). However, developing a robust MASLD/MASH mouse model with obesity and peripheral metabolic dysfunction remains a challenge. In this study, we have fed two different MASH-inducing diets to male mice with pre-existing high-fat (HF) diet-induced obesity. While a HF diet with 40% Kcal from fat (mostly corn-oil shortening), 2% cholesterol, and 22% fructose reduced adiposity in mice with pre-existing obesity, a high-fat diet with 60% Kcal from fat (mostly lard), 2% cholesterol and supplemented with 10% fructose in the drinking water (HFC+Fr diet) promoted body weight and fat mass gain. Of note, 24 weeks of the HFC+Fr diet induced obesity, metabolic dysfunction, liver steatosis, and increased the expression of hepatic peroxisome proliferator-activated receptor  ( Pparg, PPARG) in both male and female mice. However, HFC+Fr diet promoted MASH with fibrosis only in male mice, which was reduced by the knockout of Pparg in hepatocytes ( Pparg ΔHep ). In addition, the expression of key hepatic genes involved in methionine metabolism was downregulated by the HFC+Fr diet in control male mice, whereas Pparg ΔHep upregulated their expression. Overall, the HFC+Fr diet is obesogenic and promotes MASLD in both male and female mice. However, the HFC+Fr diet promotes MASH in a sex- and hepatocyte PPARG-specific manner, which may be associated with downregulation of genes involved in hepatic methionine metabolism.