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

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.

• Authors: Zeyneb Kurt, Rio Barrere-Cain, Jonnby LaGuardia, Margarete Mehrabian, Calvin Pan, Simon T Hui, Frode Norheim, Zhiqiang Zhou, Yehudit Hasin, Aldons J Lusis, Xia Yang
• Journal: Biology of sex differences (Biol Sex Differ) Vol. 9 Issue 1 Pg. 46 (10 22 2018) ISSN: 2042-6410 [Electronic] England
• PMID: 30343673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Adipose Tissue (metabolism)
• Animals
• Castration
• Female
• Genomics
• Lipid Metabolism
• Liver (metabolism)
• Male
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Sex Characteristics
• Signal Transduction
• Transcriptome