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.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.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.These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.NCT02390232.
Sarra Smati, Arnaud Polizzi, Anne Fougerat, Sandrine Ellero-Simatos, Yuna Blum, Yannick Lippi, Marion Régnier, Alexia Laroyenne, Marine Huillet, Muhammad Arif, Cheng Zhang, Frederic Lasserre, Alain Marrot, Talal Al Saati, JingHong Wan, Caroline Sommer, Claire Naylies, Aurelie Batut, Celine Lukowicz, Tiffany Fougeray, Blandine Tramunt, Patricia Dubot, Lorraine Smith, Justine Bertrand-Michel, Nathalie Hennuyer, Jean-Philippe Pradere, Bart Staels, Remy Burcelin, Françoise Lenfant, Jean-François Arnal, Thierry Levade, Laurence Gamet-Payrastre, Sandrine Lagarrigue, Nicolas Loiseau, Sophie Lotersztajn, Catherine Postic, Walter Wahli, Christophe Bureau, Maeva Guillaume, Adil Mardinoglu, Alexandra Montagner, Pierre Gourdy, Hervé Guillou