PT - JOURNAL ARTICLE AU - Sarra Smati AU - Arnaud Polizzi AU - Anne Fougerat AU - Sandrine Ellero-Simatos AU - Yuna Blum AU - Yannick Lippi AU - Marion Régnier AU - Alexia Laroyenne AU - Marine Huillet AU - Muhammad Arif AU - Cheng Zhang AU - Frederic Lasserre AU - Alain Marrot AU - Talal Al Saati AU - JingHong Wan AU - Caroline Sommer AU - Claire Naylies AU - Aurelie Batut AU - Celine Lukowicz AU - Tiffany Fougeray AU - Blandine Tramunt AU - Patricia Dubot AU - Lorraine Smith AU - Justine Bertrand-Michel AU - Nathalie Hennuyer AU - Jean-Philippe Pradere AU - Bart Staels AU - Remy Burcelin AU - Françoise Lenfant AU - Jean-François Arnal AU - Thierry Levade AU - Laurence Gamet-Payrastre AU - Sandrine Lagarrigue AU - Nicolas Loiseau AU - Sophie Lotersztajn AU - Catherine Postic AU - Walter Wahli AU - Christophe Bureau AU - Maeva Guillaume AU - Adil Mardinoglu AU - Alexandra Montagner AU - Pierre Gourdy AU - Hervé Guillou TI - Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target AID - 10.1136/gutjnl-2020-323323 DP - 2021 Apr 26 TA - Gut PG - gutjnl-2020-323323 4099 - http://gut.bmj.com/content/early/2021/04/26/gutjnl-2020-323323.short 4100 - http://gut.bmj.com/content/early/2021/04/26/gutjnl-2020-323323.full AB - 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.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.