Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)

Abstract

Background and Aims Nonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published “omics”‐defined NASH signatures. Approach and Results Here, we have explored transcriptomic profiles of livers starting from a 910‐obese‐patient cohort, which was further stratified based on stringent histological characterization, to define “NoNASH” and “NASH” patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF‐calculated gene signatures identified NASH patients in independent cohorts with high accuracy. Conclusions This large‐scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.

Hepatic steatosis and steatohepatitis: a functional meta-analysis of sex-based differences in transcriptomic studies

“…The vinculin cytoplasmic actin-binding protein is enriched in focal adhesions and adherens junctions to contribute to junction stability [40] and plays a vital role as a regulator of apoptosis [41]. Of note, although "cellular adhesion" represents a broad set of processes rather than a specific biologic pathway, this term was previously reported as a GO term consistently enriched in male NASH patients [42]. Furthermore, Arendt et al identified differentially expressed genes related to cell-cell adhesion (ANXA2 and MAG) between NAFL and NASH patients [34].…”

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

“…However, the incidence of NAFLD increases in women after menopause, suggesting a protective role of estrogens [ 8 ]. Sex-specific NASH signatures were recently identified in human liver, suggesting that NASH is a sexually dimorphic disease [ 9 ].…”

Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology

“…Likewise, a recent study that involved large-scale analysis of transcriptomic profiles from human livers suggested the sexually dimorphic nature of NASH and its link with fibrosis and responses to drugs. 55 Unrevealing the genetic mechanisms that contribute to sex-spe-cific NAFLD risk should be urgently addressed in further candidate gene association or GWAS studies of NAFLD. Elucidating the sexspecific genetic architecture of NAFLD represents an important area for future research.…”