Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Issue 4 (26th April 2021)

• Record Type: Journal Article
• Authors: 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, Françoise; Arnal, Jean-François; 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;
• Is Part Of: Gut. Volume 71:Issue 4(2022)
• Page Start: 807
• Page End: 821
• Publication Date: 2021-04-26
• Subjects: nonalcoholic steatohepatitis -- liver metabolism -- lipid metabolism -- gene expression; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2020-323323
• Languages: English
• ISSNs: 0017-5749

Abstract

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 .