PMID- 26338827 OWN - NLM STAT- MEDLINE DCOM- 20170620 LR - 20220409 IS - 1468-3288 (Electronic) IS - 0017-5749 (Print) IS - 0017-5749 (Linking) VI - 65 IP - 11 DP - 2016 Nov TI - Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARalpha expression. PG - 1882-1894 LID - 10.1136/gutjnl-2014-308883 [doi] AB - 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 alpha (PPARalpha)-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. PPARalpha, 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 PPARalpha-deficient mice. CONCLUSIONS: MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARalpha expression. Antagomir-21 might be a future therapeutic strategy for NASH. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. FAU - Loyer, Xavier AU - Loyer X AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Paradis, Valerie AU - Paradis V AD - Service d'Anatomie Pathologique, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. AD - INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3, Clichy, France. AD - Universite Denis Diderot-Paris 7, Sorbonne Paris Cite, Paris, France. FAU - Henique, Carole AU - Henique C AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Vion, Anne-Clemence AU - Vion AC AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Colnot, Nathalie AU - Colnot N AD - Service d'Anatomie Pathologique, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. FAU - Guerin, Coralie L AU - Guerin CL AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Devue, Cecile AU - Devue C AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - On, Sissi AU - On S AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Scetbun, Jeremy AU - Scetbun J AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Romain, Melissa AU - Romain M AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Paul, Jean-Louis AU - Paul JL AD - Service de Biochimie, Hopital Europeen Georges Pompidou, AP-HP (Assistance Publique-Hopitaux de Paris), Paris, France. FAU - Rothenberg, Marc E AU - Rothenberg ME AD - Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. FAU - Marcellin, Patrick AU - Marcellin P AD - INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3, Clichy, France. AD - Universite Denis Diderot-Paris 7, Sorbonne Paris Cite, Paris, France. AD - Service d'Hepatologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. FAU - Durand, Francois AU - Durand F AD - INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3, Clichy, France. AD - Universite Denis Diderot-Paris 7, Sorbonne Paris Cite, Paris, France. AD - Service d'Hepatologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. FAU - Bedossa, Pierre AU - Bedossa P AD - Service d'Anatomie Pathologique, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. AD - INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3, Clichy, France. AD - Universite Denis Diderot-Paris 7, Sorbonne Paris Cite, Paris, France. FAU - Prip-Buus, Carina AU - Prip-Buus C AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. AD - INSERM, U1016, Institut Cochin, Paris, France. AD - CNRS, UMR8104, Paris, France. FAU - Bauge, Eric AU - Bauge E AD - Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID, Lille, France. FAU - Staels, Bart AU - Staels B AD - Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID, Lille, France. FAU - Boulanger, Chantal M AU - Boulanger CM AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Tedgui, Alain AU - Tedgui A AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Rautou, Pierre-Emmanuel AU - Rautou PE AD - INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France. AD - Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. AD - Universite Denis Diderot-Paris 7, Sorbonne Paris Cite, Paris, France. AD - Service d'Hepatologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Clichy, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150903 PL - England TA - Gut JT - Gut JID - 2985108R RN - 0 (Lipoproteins, LDL) RN - 0 (MIRN21 microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (Oligonucleotides) RN - 0 (PPAR alpha) SB - IM CIN - doi: 10.1136/gutjnl-2015-310044 MH - Animals MH - Diet, High-Fat MH - Gene Expression Profiling/methods MH - Hepatocytes/metabolism/pathology MH - Humans MH - Lipid Metabolism MH - Lipoproteins, LDL/metabolism MH - Mice MH - MicroRNAs/antagonists & inhibitors/*metabolism MH - *Non-alcoholic Fatty Liver Disease/metabolism/prevention & control MH - *Oligonucleotides/metabolism/pharmacology MH - PPAR alpha/antagonists & inhibitors/*metabolism PMC - PMC5099209 OTO - NOTNLM OT - FATTY LIVER OT - INFLAMMATION OT - NONALCOHOLIC STEATOHEPATITIS COIS- Competing interests: None declared. EDAT- 2015/09/05 06:00 MHDA- 2017/06/21 06:00 PMCR- 2016/11/08 CRDT- 2015/09/05 06:00 PHST- 2014/11/24 00:00 [received] PHST- 2015/08/09 00:00 [revised] PHST- 2015/08/13 00:00 [accepted] PHST- 2015/09/05 06:00 [pubmed] PHST- 2017/06/21 06:00 [medline] PHST- 2015/09/05 06:00 [entrez] PHST- 2016/11/08 00:00 [pmc-release] AID - gutjnl-2014-308883 [pii] AID - 10.1136/gutjnl-2014-308883 [doi] PST - ppublish SO - Gut. 2016 Nov;65(11):1882-1894. doi: 10.1136/gutjnl-2014-308883. Epub 2015 Sep 3.