دورية أكاديمية
Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
| العنوان: | Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target |
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| المؤلفون: | 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 |
| بيانات النشر: | BMJ Publishing Group |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | gene expression, lipid metabolism, liver metabolism, nonalcoholic steatohepatitis, Sciences du Vivant [q-bio], Sciences du Vivant [q-bio]/Alimentation et Nutrition |
| الوصف: | 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 . |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0017-5749 |
| العلاقة: | https://oskar-bordeaux.fr/handle/20.500.12278/33440Test |
| DOI: | 10.1136/gutjnl-2020-323323 |
| الإتاحة: | https://doi.org/20.500.12278/33440Test https://doi.org/10.1136/gutjnl-2020-323323Test https://oskar-bordeaux.fr/handle/20.500.12278/33440Test https://hdl.handle.net/20.500.12278/33440Test |
| رقم الانضمام: | edsbas.A3E84683 |
| قاعدة البيانات: | BASE |
| تدمد: | 00175749 |
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| DOI: | 10.1136/gutjnl-2020-323323 |