Article Text
Abstract
Objective We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.
Design Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.
Results The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.
Conclusions These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.
Trial registration number NCT02390232.
- nonalcoholic steatohepatitis
- liver metabolism
- lipid metabolism
- gene expression
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All of the liver gene expression profiling are deposited on public database (Gene expression omnibus). Any other data will be made available on request.
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Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All of the liver gene expression profiling are deposited on public database (Gene expression omnibus). Any other data will be made available on request.
Footnotes
PG and HG contributed equally.
Contributors SS designed experiments, performed experiments, analysed the data and wrote the paper. AP, AF, SE-S, YB, YL and MR contributed to design experiments, performed experiments and analysed the data. AL, MH, FL, AMarr, TAS, JW, CS, CN, AB, CL, TF, BT, PD, LS and JBM performed experiments and contributed to data analysis. MA and CZ analysed the data. NH, J-PP, BS, RB, FL, J-FA, TL, LGP, SLa, NL, SLo, CP, WW, CB and AMard provided critical materials, supervised experiments and contributed to data analysis. MG provided critical reagents, contributed to design the project and to data analysis. AMon and PG designed the project, supervised experiments, analysed the data and wrote the paper. HG designed the project, supervised experiments, performed experiments, analysed the data and wrote the paper.
Funding SS was supported by a PhD grant from INSERM. AF was supported by a postdoctoral fellowship from Agreenskills. AL was supported by a grant from SNFGE. PG, BT and AMon were supported by grants from the “Société Francophone du Diabète”, the “Société Française d’Endocrinologie” and the “Société Française de Nutrition”. This work was funded by JPI Fatmal (RB, AMon, PG, SES, HG). WW, AMon, NL, PG and HG were supported by grants from the Région Occitanie. MG, CB, AMon, PG and HG were supported by a grant from AFEF. CP, AMon, PG and HG were supported by a grant from ANR (Hepatomorphic).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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