Sex Differences in NASH Pathways Informed by Multiomics

Nonalcoholic fatty liver disease (NAFLD) has presented itself as a significant health burden, with increasing prevalence globally and evidence of a sexually dimorphic disease course. Particularly, it is of critical importance to understand the latter stage of disease, nonalcoholic steatohepatitis (NASH) with fibrosis, which is more prevalent and severe in males, in order to provide better prevention, treatment, and biomarker options to reduce the health burden. Our mechanistic understanding of NASH progression is far from elucidated, and thus, we present a multi-omics pathway and network analysis utilizing genomic, transcriptomic, and lipidomic data from the Hybrid Mouse Diversity Panel (HMDP) to uncover key biological processes and key driver genes causal to liver fibrosis and to dissect sex differences. Analyzing these multi-omics datasets by sex, we present mechanistic differences important to fibrosis development between males and females. We find that males present with greater enrichment of immune processes as well as abnormalities in protein and lipid metabolism, whereas females present with significant abnormalities linked with carbohydrate metabolism processes, suggesting differential causal mechanisms of fibrosis progression between sexes. Comparing males and females, we also find consistent processes such as extracellular matrix development, clearly vital for fibrosis to develop. Using gene regulatory network analysis of the liver tissue, we further identified key network genes driving the sex-specific processes as well as those consistent between sexes that are important for liver fibrosis. Our multi-omics integrative studies offer comprehensive understanding of NASH in a sex-specific manner. Disclosure M. Blencowe: None. A. Lusis: None. F. Norheim: None. Z. Saleem: None. N. S. Hsu: None. S. Hui: None. C. Pan: None. K. Chella krishnan: None. C. Edillor: None. X. Yang: None. Funding National Institutes of Health (R01DK117850)