Details

Autor(en) / Beteiligte

• Smati, Sarra
• Polizzi, Arnaud
• Fougerat, Anne
• Ellero-Simatos, Sandrine
• Blum, Yuna
• Lippi, Yannick
• Régnier, Marion
• Laroyenne, Alexia
• Huillet, Marine
• Arif, Muhammad
• Zhang, Cheng
• Lasserre, Frederic
• Marrot, Alain
• Al Saati, Talal
• Wan, JingHong
• Sommer, Caroline
• Naylies, Claire
• Batut, Aurelie
• Lukowicz, Celine
• Fougeray, Tiffany
• Tramunt, Blandine
• Dubot, Patricia
• Smith, Lorraine
• Bertrand-Michel, Justine
• Hennuyer, Nathalie
• Pradere, Jean-Philippe
• Staels, Bart
• Burcelin, Remy
• Lenfant, Françoise
• Arnal, Jean-François
• Levade, Thierry
• Gamet-Payrastre, Laurence
• Lagarrigue, Sandrine
• Loiseau, Nicolas
• Lotersztajn, Sophie
• Postic, Catherine
• Wahli, Walter
• Bureau, Christophe
• Guillaume, Maeva
• Mardinoglu, Adil
• Montagner, Alexandra
• Gourdy, Pierre
• Guillou, Hervé

Titel

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

Ist Teil von

• Gut, 2022-04, Vol.71 (4), p.807-821

Ort / Verlag

England: BMJ Publishing Group Ltd and British Society of Gastroenterology

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• ObjectiveWe 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.DesignDifferent 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.ResultsThe 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.ConclusionsThese 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.