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

Sarra Smati 1, 2 Arnaud Polizzi 3 Anne Fougerat 3 Sandrine Ellero-Simatos 3 Yuna Blum 4, 5 Yannick Lippi 6 Marion Régnier 1 Alexia Laroyenne 1 Marine Huillet 3 Muhammad Arif 7 Cheng Zhang 7 Frédéric Lasserre 3 Alain Marrot 1 Talal Al Saati 8 Jinghong Wan 9 Caroline Sommer 10 Claire Naylies 6 Aurelie Batut 2 Céline Lukowicz 1 Tiffany Fougeray 3 Blandine Tramunt 2 Patricia Dubot 11 Lorraine Smith 3 Justine Bertrand-Michel 2 Nathalie Hennuyer 12 Jean-Philippe Pradere 2 Bart Staels 12 Remy Burcelin 2 Françoise Lenfant 2 Jean-François Arnal 2 Thierry Levade 11 Laurence Gamet-Payrastre 3 Sandrine Lagarrigue 13 Nicolas Loiseau 3 Sophie Lotersztajn 9 Catherine Postic 14 Walter Wahli 1, 15, 16 Christophe Bureau 17 Maeva Guillaume 17 Adil Mardinoglu 7 Alexandra Montagner 2 Pierre Gourdy 2, * Hervé Guillou 3, * 
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. Trial registration number NCT02390232 .
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https://hal.inrae.fr/hal-03215969
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Submitted on : Wednesday, May 11, 2022 - 9:53:34 AM
Last modification on : Thursday, September 8, 2022 - 5:39:19 PM

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Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License

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Sarra Smati, Arnaud Polizzi, Anne Fougerat, Sandrine Ellero-Simatos, Yuna Blum, et al.. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut, BMJ Publishing Group, 2022, 71, pp.807-821. ⟨10.1136/gutjnl-2020-323323⟩. ⟨hal-03215969⟩

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