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  • Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression

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Hepatology
Original article
Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression
  1. Xavier Loyer1,2,
  2. Valérie Paradis3,4,5,
  3. Carole Hénique1,2,
  4. Anne-Clémence Vion1,2,
  5. Nathalie Colnot3,
  6. Coralie L Guerin1,2,
  7. Cécile Devue1,2,
  8. Sissi On1,2,
  9. Jérémy Scetbun1,2,
  10. Mélissa Romain1,2,
  11. Jean-Louis Paul6,
  12. Marc E Rothenberg7,
  13. Patrick Marcellin4,5,8,
  14. François Durand4,5,8,
  15. Pierre Bedossa3,4,5,
  16. Carina Prip-Buus2,9,10,
  17. Eric Baugé11,
  18. Bart Staels11,
  19. Chantal M Boulanger1,2,
  20. Alain Tedgui1,2,
  21. Pierre-Emmanuel Rautou1,2,5,8
  1. 1INSERM, U970, Paris Cardiovascular Research Center—PARCC, Paris, France
  2. 2Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  3. 3Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
  4. 4INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy, France
  5. 5Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France
  6. 6Service de Biochimie, Hôpital Européen Georges Pompidou, AP-HP (Assistance Publique-Hôpitaux de Paris), Paris, France
  7. 7Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  8. 8Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
  9. 9INSERM, U1016, Institut Cochin, Paris, France
  10. 10CNRS, UMR8104, Paris, France
  11. 11Univ. Lille, Inserm, Institut Pasteur de Lille, U1011—EGID, Lille, France
  1. Correspondence to Dr Pierre-Emmanuel Rautou, Paris—Centre de recherche Cardiovasculaire à l'HEGP, INSERM—U970, 56, rue Leblanc, 75373 Paris, cedex 15, France; pierre-emmanuel.rautou{at}inserm.fr

Abstract

Objective Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH.

Design We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient (Ldlr−/−) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined.

Results Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr−/− fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice.

Conclusions MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH.

  • FATTY LIVER
  • INFLAMMATION
  • NONALCOHOLIC STEATOHEPATITIS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2014-308883

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    Footnotes

    • Correction notice This article has been corrected since it published Online First. The Open Access licence has been added.

    • Contributors XL, P-ER, and AT obtained funding, conceived and designed the study, and interpreted the data. XL and P-ER drafted the manuscript. P-ER collected the patients clinical and laboratory data. CMB and AT contributed to the writing of the manuscript. XL, A-CV, CH, NC, CLG, CD, SO, JS, MR and J-LP carried out experiments and analysed the data. MER provided miR-21−/− mice. CPB carried out hepatic ketonic bodies measurement and discussed data and manuscript. EB and BS provided Pparα−/− mice and discussed the data and the manuscript. PM, FD, PB and VP provided liver samples and contributed to the analysis of the data. All authors critically revised the manuscript and approved its final version.

    • Funding This work was supported by ‘appel à projets scientifiques de Sorbonne Paris Cité 2012’, ANR 11-META-004-02 MIRA, Fondation de France (2012-00029497) and Institut National de la Santé et de la Recherche Médicale (INSERM). XL was supported by ‘Fondation pour la Recherche Médicale’ (FRM), ‘Fondation Lefoulon-Delalande’ and ANR-Meta-2011-miR-A. P-ER was supported by ‘bourse Robert Tournut’ of the Société Nationale Française de Gastroentérologie (SNFGE) and the Association Française pour l'Etude du foie (AFEF), and A-CV by a grant from Région Ile-de-France (CODDIM).

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

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

    • Data sharing statement We agree to share all primary data and protocols employed in this study.

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