Gut.: co-auth.: W.Wahli

Gut. 2021 Apr 26;gutjnl-2020-323323. doi: 10.1136/gutjnl-2020-323323. Online ahead of print.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Sarra Smati 1 2Arnaud Polizzi 1Anne Fougerat 1Sandrine Ellero-Simatos 1Yuna Blum 3 4Yannick Lippi 1Marion Régnier 1Alexia Laroyenne 1Marine Huillet 1Muhammad Arif 5Cheng Zhang 5Frederic Lasserre 1Alain Marrot 1Talal Al Saati 6JingHong Wan 7 8Caroline Sommer 1Claire Naylies 1Aurelie Batut 2Celine Lukowicz 1Tiffany Fougeray 1Blandine Tramunt 2Patricia Dubot 9 10Lorraine Smith 1Justine Bertrand-Michel 2Nathalie Hennuyer 11Jean-Philippe Pradere 2Bart Staels 11Remy Burcelin 2Françoise Lenfant 2Jean-François Arnal 2Thierry Levade 9 10Laurence Gamet-Payrastre 1Sandrine Lagarrigue 12Nicolas Loiseau 1Sophie Lotersztajn 7 8Catherine Postic 13Walter Wahli 1 14 15Christophe Bureau 16Maeva Guillaume 16Adil Mardinoglu 5 17Alexandra Montagner 2Pierre Gourdy # 18 19Hervé Guillou # 20Affiliations expand


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.