دورية
Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
| العنوان: | Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target |
|---|---|
| المؤلفون: | Smati, Sarra, Polizzi, Arnaud, Fougerat, Anne, Ellero-Simatos, Sandrine, Blum, Yuna, Lippi, Yannick, Régnier, Marion, Laroyenne, Alexia, Huillet, Marine, Arif, Muhammad, Zhang, Cheng, Lasserre, Frederic, Marrot, Alain, Al Saati, Talal, Wan, JingHong, Sommer, Caroline, Naylies, Claire, Batut, Aurelie, Lukowicz, Celine, Fougeray, Tiffany, Tramunt, Blandine, Dubot, Patricia, Smith, Lorraine, Bertrand-Michel, Justine, Hennuyer, Nathalie, Pradere, Jean-Philippe, Staels, Bart, Burcelin, Remy, Lenfant, Francoise, Arnal, Jean-Francois, Levade, Thierry, Gamet-Payrastre, Laurence, Lagarrigue, Sandrine, Loiseau, Nicolas, Lotersztajn, Sophie, Postic, Catherine, Wahli, Walter, Bureau, Christophe, Guillaume, Maeva, Mardinoglu, Adil, Montagner, Alexandra, Gourdy, Pierre, Guillou, Hervé |
| المصدر: | Gut; 2022, Vol. 71 Issue: 4 p807-821, 15p |
| مستخلص: | 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 00175749 14683288 |
|---|---|
| DOI: | 10.1136/gutjnl-2020-323323 |