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

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-...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099209/
https://www.ncbi.nlm.nih.gov/pubmed/26338827
http://dx.doi.org/10.1136/gutjnl-2014-308883
Descripción
Sumario: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.