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



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.



Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation inLdlr-/-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.



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.
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Xavier
X
Loyer
Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.|INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy, France.|Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France.
Valérie
V
Paradis
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Carole
C
Hénique
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Anne-Clémence
AC
Vion
Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
Nathalie
N
Colnot
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Coralie L
CL
Guerin
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Cécile
C
Devue
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Sissi
S
On
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Jérémy
J
Scetbun
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Mélissa
M
Romain
Service de Biochimie, Hôpital Européen Georges Pompidou, AP-HP (Assistance Publique-Hôpitaux de Paris), Paris, France.
Jean-Louis
JL
Paul
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Marc E
ME
Rothenberg
INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy, France.|Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France.|Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
Patrick
P
Marcellin
INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy, France.|Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France.|Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
François
F
Durand
Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.|INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy, France.|Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France.
Pierre
P
Bedossa
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.
Carina
C
Prip-Buus
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID, Lille, France.
Eric
E
Baugé
Univ. Lille, Inserm, Institut Pasteur de Lille, U1011-EGID, Lille, France.
Bart
B
Staels
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Chantal M
CM
Boulanger
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Alain
A
Tedgui
INSERM, U970, Paris Cardiovascular Research Center-PARCC, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France.|Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
Pierre-Emmanuel
PE
Rautou
D000818:Animals; D059305:Diet, High-Fat; D020869:Gene Expression Profiling / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000517:prevention & control; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D008077:Lipoproteins, LDL; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; D047493:PPAR alpha
FATTY LIVER; INFLAMMATION; NONALCOHOLIC STEATOHEPATITIS