Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)
Open Access
- 1 March 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 73 (3), 920-936
- https://doi.org/10.1002/hep.31312
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.Funding Information
- Fondation pour la Recherche Médicale (DEQ20150331724)
- Fondation de France (2014‐00047965)
This publication has 50 references indexed in Scilit:
- DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric SurgeryCell Metabolism, 2013
- Overview of random forest methodology and practical guidance with emphasis on computational biology and bioinformaticsWIREs Data Mining and Knowledge Discovery, 2012
- Obesity-Dependent Metabolic Signatures Associated with Nonalcoholic Fatty Liver Disease ProgressionJournal of Proteome Research, 2012
- Prevalence, gender, ethnic variations, and prognosis of NASHThe Esophagus, 2010
- Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitisJournal of Hepatology, 2009
- How growth hormone controls growth, obesity and sexual dimorphismTrends in Genetics, 2008
- Logistic regression for disease classification using microarray data: model selection in a largepand smallncaseBioinformatics, 2007
- Thousands of samples are needed to generate a robust gene list for predicting outcome in cancerProceedings of the National Academy of Sciences of the United States of America, 2006
- Design and validation of a histological scoring system for nonalcoholic fatty liver diseaseHepatology, 2005
- Use and Abuse of HOMA ModelingDiabetes Care, 2004