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Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
- Source :
- Gut; 2022, Vol. 71 Issue: 4 p807-821, 15p
- Publication Year :
- 2022
-
Abstract
- ObjectiveWe 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.DesignDifferent 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.ResultsThe 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.ConclusionsThese findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.Trial registration numberNCT02390232.
Details
- Language :
- English
- ISSN :
- 00175749 and 14683288
- Volume :
- 71
- Issue :
- 4
- Database :
- Supplemental Index
- Journal :
- Gut
- Publication Type :
- Periodical
- Accession number :
- ejs59106864
- Full Text :
- https://doi.org/10.1136/gutjnl-2020-323323