Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Issue 11 (3rd September 2015)

• Record Type: Journal Article
• Authors: Loyer, Xavier; Paradis, Valérie; Hénique, Carole; Vion, Anne-Clémence; Colnot, Nathalie; Guerin, Coralie L; Devue, Cécile; On, Sissi; Scetbun, Jérémy; Romain, Mélissa; Paul, Jean-Louis; Rothenberg, Marc E; Marcellin, Patrick; Durand, François; Bedossa, Pierre; Prip-Buus, Carina; Baugé, Eric; Staels, Bart; Boulanger, Chantal M; Tedgui, Alain; Rautou, Pierre-Emmanuel
• Is Part Of: Gut. Volume 65:Issue 11(2016)
• Page Start: 1882
• Page End: 1894
• Publication Date: 2015-09-03
• Subjects: FATTY LIVER -- INFLAMMATION -- NONALCOHOLIC STEATOHEPATITIS; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2014-308883
• Languages: English
• ISSNs: 0017-5749

Abstract

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.