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

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.

• PMID: 33903148
• DOI: 10.1136/gutjnl-2020-323323