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Article Dans Une Revue Gut Année : 2022

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

Anne Fougerat
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Yannick Lippi
Marion Régnier
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Alexia Laroyenne
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Muhammad Arif
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Frédéric Lasserre
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Alain Marrot
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Talal Al Saati
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Caroline Sommer
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Claire Naylies
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Céline Lukowicz
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Nicolas Loiseau
Catherine Postic
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Résumé

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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Dates et versions

hal-03215969 , version 1 (11-05-2022)

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Paternité - Pas d'utilisation commerciale

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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, 2022, 71 (4), pp.807-821. ⟨10.1136/gutjnl-2020-323323⟩. ⟨hal-03215969⟩
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