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

Xavier Loyer (1) , Valérie Paradis (2, 3) , Carole Hénique (1) , Anne-Clémence Vion (1) , Nathalie Colnot (2) , Coralie Guerin (1) , Cécile Devue (1) , Sissi On (1) , Jérémy Scetbun (1) , Mélissa Romain (1) , Jean-Louis Paul (4) , Marc Rothenberg (5) , Patrick Marcellin (3, 2) , François Durand (3, 2) , Pierre Bedossa (2, 3) , Carina Prip-Buus (6) , Eric Baugé (7) , Bart Staels (7) , Chantal Boulanger (1) , Alain Tedgui (1) , Pierre-Emmanuel Rautou (1, 2)

1 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
2 Hôpital Beaujon [AP-HP]
3 CRB3 - Centre de recherche biomédicale Bichat-Beaujon
4 HEGP - Hôpital Européen Georges Pompidou [APHP]
5 University of Cincinnati College of Medicine
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 RNMCD - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011

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.

Mots clés: FATTY LIVER; INFLAMMATION; NONALCOHOLIC STEATOHEPATITIS

Domaines: Hépatologie et Gastroentérologie

Xavier Loyer, Valérie Paradis, Carole Hénique, Anne-Clémence Vion, Nathalie Colnot, et al.. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Gut, 2016, 65 (11), pp.1882-1894. ⟨10.1136/gutjnl-2014-308883⟩. ⟨hal-03367435⟩