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 (PpargΔHep). In addition, the expression of key hepatic genes involved in methionine metabolism was downregulated by the HFC+Fr diet in control male mice, whereas PpargΔHep 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.