SUN-117 Gender-Dependent Effect of Hepatocyte PPARg in a Model of MASH with Obesity and Insulin Resistance.

Abstract I. Hawro: None. M. Sierra-Cruz: None. S.M. Lee: None. J.T. Muratalla: None. J. Cordoba-Chacon: None. Patients with obesity and insulin resistance have a high prevalence of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and steatohepatitis (MASH). We reported that hepatic peroxisome proliferator-activated receptor γ (PPARγ) expression is increased in patients with obesity and MASH undergoing bariatric surgery. Moreover, the knockout of PPARγ gene in hepatocytes reduces MASH and increases the therapeutic effects of rosiglitazone maleate (a PPARγ agonist) in the liver. However, the special diets that induce human-like MASH in mice fail to reproduce severe obesity and insulin resistance. Furthermore, the role of PPARγ in hepatocytes in models of MASH remains controversial. In this study, we fed 10-week-old control and hepatocyte-specific PPARγ knockout (PpargΛHep) mice for 24 weeks with a high-fat diet (60% Kcal from fat and 2% cholesterol) supplemented with 10% fructose in the drinking water (HFC+Fr diet) to induce human-like MASH. The gender-dependent effects of diet and hepatocyte PPARγ on adiposity, insulin resistance, and progression of liver pathology were assessed. This HFC+Fr diet promoted obesity and insulin resistance in male and female mice. However, only HFC+Fr-fed male mice developed MASH with hepatic fibrosis. As we previously reported with different diets, PpargΛHep improved liver histology and reduced fibrosis in HFC+Fr-fed male mice without a concomitant improvement in adiposity or insulin resistance but with a surprising increase of plasma insulin level. The transcriptomic analysis of the livers confirmed the strong effect of the HFC+Fr diet on male mice with 2049 differential expressed genes (DEG, Log2FC <-1, >1, padj <0.05), as compared to the 157 DEG in female mice. Of note, hepatic PPARγ mRNA and protein expression was increased by the HFC+Fr diet in male and female obese mice. However, the expression of hepatic PPARγ-target genes Cidea, Cidec, Mogat1, Cd36, etc, was only increased in male mice. Interestingly, whereas 1728 DEG were identified between male and female PPARγ-intact mice fed an HFC+Fr diet, only 920 DEG were identified between male and female PpargΛHep mice fed an HFC+Fr diet. The difference in the number of DEG between these groups suggests that hepatocyte PPARγ reprograms the hepatic transcriptome in MASH in a gender-dependent manner. Among the top 100 upregulated DEG identified between male and female PPARγ-intact mice: Cfd, Cidea, Fabp3, Sdcbp2, and Elfn1 might be involved in fat accumulation and fibrosis, and these were not differentially expressed between male and female PpargΛHep mice. Furthermore, these genes could be direct PPAR-targets based on prediction of The PPARgene database. Overall, our study described a suitable mouse model of human-like MASLD and identified a gender-dependent regulation of hepatic genes that could be regulated by hepatocyte PPARγ to promote MASH with fibrosis. Sunday, June 2, 2024