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

Zeyneb Kurt,Zhiqiang Zhou,Calvin Pan,Margarete Mehrabian,Frode Norheim,Rio Barrere-Cain,Aldons J Lusis,Jonnby Laguardia,Simon T Hui,Xia Yang,Yehudit Hasin

doi:10.1186/s13293-018-0205-7

Zeyneb Kurt, Zhiqiang Zhou + Show 9 more

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https://doi.org/10.1186/s13293-018-0205-7

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Abstract

BackgroundNon-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.ResultsWe 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.ConclusionsOur 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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) encompasses benign steatosis and more severe conditions such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer
Tissue-specific coexpression networks in females To retrieve functional gene-gene relationships, gene coexpression networks were constructed based on transcriptome data of 206 liver and 211 adipose tissue samples of female mice from 103 hybrid mouse diversity panel (HMDP) strains using Weighted Gene Co-expression Network Analysis (WGCNA) [29] and Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) [30]
In the male HMDP data, we found similar percentages of adipose modules to be associated with NAFLD [18], but a higher percentage of NAFLD-associated liver modules (32% vs 13% for MEGENA modules and 35% vs 23% for WGCNA modules in males vs females)

Summary

Introduction

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. Nonalcoholic fatty liver disease (NAFLD) covers a wide spectrum of disorders spanning simple liver steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [1,2,3]. Males with NAFLD have more severe metabolic phenotypes than females, including higher glucose levels, higher systolic blood pressure, greater visceral adiposity, lower adiponectin levels,

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