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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 Yannick Lippi 5 Marion Régnier 2 Alexia Laroyenne 2 Marine Huillet 3 Muhammad Arif 6 Cheng Zhang 6 Frédéric Lasserre 3 Alain Marrot 2 Talal Al Saati 7 Jinghong Wan 8 Caroline Sommer 9 Claire Naylies 5 Aurelie Batut 1 Céline Lukowicz 2 Tiffany Fougeray 3 Blandine Tramunt 1 Patricia Dubot 10 Lorraine Smith 3 Justine Bertrand-Michel 1 Nathalie Hennuyer 11 Jean-Philippe Pradere 1 Bart Staels 11 Remy Burcelin 1 Françoise Lenfant 1 Jean-François Arnal 1 Thierry Levade 10 Laurence Gamet-Payrastre 3 Sandrine Lagarrigue 12 Nicolas Loiseau 3 Sophie Lotersztajn 13 Catherine Postic 14 Walter Wahli 2, 15, 16 Christophe Bureau 17 Maeva Guillaume 17 Adil Mardinoglu 6 Alexandra Montagner 1 Pierre Gourdy 1 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 : Monday, May 3, 2021 - 4:21:14 PM
Last modification on : Monday, September 13, 2021 - 10:56:34 AM

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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, 2021, pp.gutjnl-2020-323323. ⟨10.1136/gutjnl-2020-323323⟩. ⟨hal-03215969⟩

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