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
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