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Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease.

  • Author(s): Kurt, Zeyneb;
  • Barrere-Cain, Rio;
  • LaGuardia, Jonnby;
  • Mehrabian, Margarete;
  • Pan, Calvin;
  • Hui, Simon T;
  • Norheim, Frode;
  • Zhou, Zhiqiang;
  • Hasin, Yehudit;
  • Lusis, Aldons J;
  • Yang, Xia
  • et al.
Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) encompasses benign steatosis and more severe conditions such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. This chronic liver disease has a poorly understood etiology and demonstrates sexual dimorphisms. We aim to examine the molecular mechanisms underlying sexual dimorphisms in NAFLD pathogenesis through a comprehensive multi-omics study. We integrated genomics (DNA variations), transcriptomics of liver and adipose tissue, and phenotypic data of NAFLD derived from female mice of ~ 100 strains included in the hybrid mouse diversity panel (HMDP) and compared the NAFLD molecular pathways and gene networks between sexes.

Results

We identified both shared and sex-specific biological processes for NAFLD. Adaptive immunity, branched chain amino acid metabolism, oxidative phosphorylation, and cell cycle/apoptosis were shared between sexes. Among the sex-specific pathways were vitamins and cofactors metabolism and ion channel transport for females, and phospholipid, lysophospholipid, and phosphatidylinositol metabolism and insulin signaling for males. Additionally, numerous lipid and insulin-related pathways and inflammatory processes in the adipose and liver tissue appeared to show more prominent association with NAFLD in male HMDP. Using data-driven network modeling, we identified plausible sex-specific and tissue-specific regulatory genes as well as those that are shared between sexes. These key regulators orchestrate the NAFLD pathways in a sex- and tissue-specific manner. Gonadectomy experiments support that sex hormones may partially underlie the sexually dimorphic genes and pathways involved in NAFLD.

Conclusions

Our multi-omics integrative study reveals sex- and tissue-specific genes, processes, and networks underlying sexual dimorphism in NAFLD and may facilitate sex-specific precision medicine.

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