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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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.

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Most cited references 30

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): November 2016

Publication date (Electronic): 03 September 2015

Volume: 65

Issue: 11

Pages: 1882-1894

Affiliations

[1 ]INSERM, U970, Paris Cardiovascular Research Center—PARCC , Paris, France

[2 ]Université Paris Descartes, Sorbonne Paris Cité , Paris, France

[3 ]Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris , Clichy, France

[4 ]INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3 , Clichy, France

[5 ]Université Denis Diderot-Paris 7, Sorbonne Paris Cité , Paris, France

[6 ]Service de Biochimie, Hôpital Européen Georges Pompidou, AP-HP (Assistance Publique-Hôpitaux de Paris) , Paris, France

[7 ]Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, Ohio, USA

[8 ]Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris , Clichy, France

[9 ]INSERM, U1016, Institut Cochin , Paris, France

[10 ]CNRS, UMR8104 , Paris, France

[11 ]Univ. Lille, Inserm, Institut Pasteur de Lille, U1011—EGID , Lille, France

Author notes

[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@ 123456inserm.fr

Article

Publisher ID: gutjnl-2014-308883

DOI: 10.1136/gutjnl-2014-308883

PMC ID: 5099209

PubMed ID: 26338827

SO-VID: 63795adb-9a05-4818-85d7-d0ae0e15b714

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