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

Détails

ID Serval
serval:BIB_BAA595ED824C
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Compte-rendu: analyse d'une oeuvre publiée.
Collection
Publications
Institution
Titre
Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target.
Périodique
Gut
Auteur⸱e⸱s
Smati S., Polizzi A., Fougerat A., Ellero-Simatos S., Blum Y., Lippi Y., Régnier M., Laroyenne A., Huillet M., Arif M., Zhang C., Lasserre F., Marrot A., Al Saati T., Wan J., Sommer C., Naylies C., Batut A., Lukowicz C., Fougeray T., Tramunt B., Dubot P., Smith L., Bertrand-Michel J., Hennuyer N., Pradere J.P., Staels B., Burcelin R., Lenfant F., Arnal J.F., Levade T., Gamet-Payrastre L., Lagarrigue S., Loiseau N., Lotersztajn S., Postic C., Wahli W., Bureau C., Guillaume M., Mardinoglu A., Montagner A., Gourdy P., Guillou H.
ISSN
1468-3288 (Electronic)
ISSN-L
0017-5749
Statut éditorial
Publié
Date de publication
2022
Peer-reviewed
Oui
Volume
71
Numéro
4
Pages
807-821
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Résumé
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.
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.
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.
These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.
NCT02390232.
Mots-clé
gene expression, lipid metabolism, liver metabolism, nonalcoholic steatohepatitis
Pubmed
Web of science
Création de la notice
11/05/2021 8:34
Dernière modification de la notice
12/03/2022 6:29
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