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

Abstract 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, generating a clinically relevant MASLD/MASH mouse model with obesity and peripheral metabolic dysfunction remains a challenge. In this study, we fed two different MASH-inducing diets to male mice with pre-existing high-fat (HF) diet-induced obesity. While a HF diet containing 40% Kcal from fat (mostly corn-oil shortening), 2% cholesterol, and 22% fructose reduced adiposity in these mice, a high-fat diet with 60% Kcal from fat (mostly lard), containing 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, and liver steatosis in male and female mice, and promoted MASH with fibrosis in male mice. Furthermore, the HFC+Fr diet increased the expression of hepatocyte peroxisome proliferator-activated receptor γ (Pparg), but the knockout of Pparg in hepatocytes (PpargΔHep) reduced the development of MASH and fibrosis in male mice. In addition, the expression of key hepatic genes involved in methionine metabolism was downregulated by the HFC+Fr diet and upregulated by PpargΔHep only in male mice. 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 hepatic methionine metabolism. New & Noteworthy We explored how a new dietary intervention with fructose in the drinking water and added cholesterol to a high-fat diet extensively used to induce obesity and insulin resistance, promotes the onset of MASLD with obesity and metabolic dysfunction in male and female mice. This clinically relevant model of MASLD shows increased expression of hepatocyte PPARγ in both male and female mice, but only male mice have PPARγ-dependent impaired methionine metabolism and develop MASH with fibrosis. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* MSC, IH, SML are co-first authors of this study. I changed the distribution option to CC-BY