期刊
GUT
卷 65, 期 11, 页码 1882-1894出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2014-308883
关键词
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资金
- 'appel a projets scientifiques de Sorbonne Paris Cite'
- Fondation de France [2012-00029497]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- 'Fondation pour la Recherche Medicale' (FRM)
- 'Fondation Lefoulon-Delalande'
- ANR-Meta-miR-A
- 'bourse Robert Tournut' of the Societe Nationale Francaise de Gastroenterologie (SNFGE)
- Association Francaise pour l'Etude du foie (AFEF)
- Region Ile-de-France (CODDIM)
- [ANR 11-META-004-02 MIRA]
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 (PPAR alpha)-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. PPAR alpha, 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 PPAR alpha-deficient mice. Conclusions MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPAR alpha expression. Antagomir-21 might be a future therapeutic strategy for NASH.
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