RT Journal Article
SR Electronic
T1 Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1882
OP 1894
DO 10.1136/gutjnl-2014-308883
VO 65
IS 11
A1 Xavier Loyer
A1 Valérie Paradis
A1 Carole Hénique
A1 Anne-Clémence Vion
A1 Nathalie Colnot
A1 Coralie L Guerin
A1 Cécile Devue
A1 Sissi On
A1 Jérémy Scetbun
A1 Mélissa Romain
A1 Jean-Louis Paul
A1 Marc E Rothenberg
A1 Patrick Marcellin
A1 François Durand
A1 Pierre Bedossa
A1 Carina Prip-Buus
A1 Eric Baugé
A1 Bart Staels
A1 Chantal M Boulanger
A1 Alain Tedgui
A1 Pierre-Emmanuel Rautou
YR 2016
UL http://gut.bmj.com/content/65/11/1882.abstract
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 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.