Hepatic molecular signatures highlight the sexual dimorphism of Non‐Alcoholic SteatoHepatitis (NASH)

BACKGROUND AND AIMS: Non-Alcoholic SteatoHepatitis (NASH) is considered as a pivotal stage in Non-Alcoholic Fatty Liver Disease (NAFLD) progression, as it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multi-factorial 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…), 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 & 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 to 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.