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Original research
Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
  1. Sarra Smati1,2,
  2. Arnaud Polizzi1,
  3. Anne Fougerat1,
  4. Sandrine Ellero-Simatos1,
  5. Yuna Blum3,4,
  6. Yannick Lippi1,
  7. Marion Régnier1,
  8. Alexia Laroyenne1,
  9. Marine Huillet1,
  10. Muhammad Arif5,
  11. Cheng Zhang5,
  12. Frederic Lasserre1,
  13. Alain Marrot1,
  14. Talal Al Saati6,
  15. JingHong Wan7,8,
  16. Caroline Sommer1,
  17. Claire Naylies1,
  18. Aurelie Batut2,
  19. Celine Lukowicz1,
  20. Tiffany Fougeray1,
  21. Blandine Tramunt2,
  22. Patricia Dubot9,10,
  23. Lorraine Smith1,
  24. Justine Bertrand-Michel2,
  25. Nathalie Hennuyer11,
  26. Jean-Philippe Pradere2,
  27. Bart Staels11,
  28. Remy Burcelin2,
  29. Françoise Lenfant2,
  30. Jean-François Arnal2,
  31. Thierry Levade9,10,
  32. Laurence Gamet-Payrastre1,
  33. Sandrine Lagarrigue12,
  34. Nicolas Loiseau1,
  35. Sophie Lotersztajn7,8,
  36. Catherine Postic13,
  37. Walter Wahli1,14,15,
  38. Christophe Bureau16,
  39. Maeva Guillaume16,
  40. Adil Mardinoglu5,17,
  41. Alexandra Montagner2,
  42. Pierre Gourdy2,18,
  43. Hervé Guillou1
  1. 1Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
  2. 2Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), UMR1297, INSERM/UPS, Université de Toulouse, Toulouse, France
  3. 3CIT, Ligue Nationale Contre Le Cancer, Paris, France
  4. 4IGDR UMR 6290, CNRS, Université de Rennes 1, Rennes, France
  5. 5Science for Life Laboratory, KTH-Royal Institute of Technology, Solna, Sweden
  6. 6Experimental Histopathology Department, INSERM US006-CREFRE, University Hospital of Toulouse, Toulouse, France
  7. 7INSERM-UMR1149, Centre de Recherche sur l'Inflammation, Paris, France
  8. 8Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
  9. 9Laboratoire de Biochimie Métabolique, CHU Toulouse, Toulouse, France
  10. 10INSERM U1037, CRCT, Université Paul Sabatier, Toulouse, France
  11. 11Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France
  12. 12INRAE, INSTITUT AGRO, PEGASE UMR1348, 35590, Saint-Gilles, France
  13. 13Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
  14. 14Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
  15. 15Center for Integrative Genomics, University of Lausanne, Le Génopode, Lausanne, Switzerland
  16. 16Hepatology Unit, Rangueil Hospital Toulouse, Paul Sabatier University Toulouse 3, Toulouse, France
  17. 17Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
  18. 18Endocrinology-Diabetology-Nutrition Department, Toulouse University Hospital, Toulouse, France
  1. Correspondence to Dr Hervé Guillou, Toxalim, INRAE, Toulouse, Occitanie, France; herve.guillou{at}inrae.fr; Professor Pierre Gourdy; pierre.gourdy{at}inserm.fr

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.

  • nonalcoholic steatohepatitis
  • liver metabolism
  • lipid metabolism
  • gene expression

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All of the liver gene expression profiling are deposited on public database (Gene expression omnibus). Any other data will be made available on request.

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Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All of the liver gene expression profiling are deposited on public database (Gene expression omnibus). Any other data will be made available on request.

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Footnotes

  • PG and HG contributed equally.

  • Contributors SS designed experiments, performed experiments, analysed the data and wrote the paper. AP, AF, SE-S, YB, YL and MR contributed to design experiments, performed experiments and analysed the data. AL, MH, FL, AMarr, TAS, JW, CS, CN, AB, CL, TF, BT, PD, LS and JBM performed experiments and contributed to data analysis. MA and CZ analysed the data. NH, J-PP, BS, RB, FL, J-FA, TL, LGP, SLa, NL, SLo, CP, WW, CB and AMard provided critical materials, supervised experiments and contributed to data analysis. MG provided critical reagents, contributed to design the project and to data analysis. AMon and PG designed the project, supervised experiments, analysed the data and wrote the paper. HG designed the project, supervised experiments, performed experiments, analysed the data and wrote the paper.

  • Funding SS was supported by a PhD grant from INSERM. AF was supported by a postdoctoral fellowship from Agreenskills. AL was supported by a grant from SNFGE. PG, BT and AMon were supported by grants from the “Société Francophone du Diabète”, the “Société Française d’Endocrinologie” and the “Société Française de Nutrition”. This work was funded by JPI Fatmal (RB, AMon, PG, SES, HG). WW, AMon, NL, PG and HG were supported by grants from the Région Occitanie. MG, CB, AMon, PG and HG were supported by a grant from AFEF. CP, AMon, PG and HG were supported by a grant from ANR (Hepatomorphic).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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