1. Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation
- Author
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Juan José Lozano, Pau Sancho-Bru, Delia Blaya, Daniel Rodrigo-Torres, Pere Ginès, José Altamirano, Ramon Bataller, Mar Coll, Joan Clària, Marta Llopis, Beatriz Aguilar-Bravo, Juan Caballería, L. Perea, Isabel Graupera, Maria Vila-Casadesús, Alba Díaz, and Jesus M. Banales
- Subjects
Adult ,Male ,0301 basic medicine ,Alcoholic liver disease ,Pathology ,medicine.medical_specialty ,Statistics as Topic ,Alcoholic hepatitis ,Biology ,Severity of Illness Index ,Mice ,03 medical and health sciences ,Liver disease ,Liver Function Tests ,Cholestasis ,Non-alcoholic Fatty Liver Disease ,Fibrosis ,microRNA ,medicine ,Animals ,Humans ,Liver injury ,Hepatitis, Alcoholic ,Gene Expression Profiling ,Gastroenterology ,Middle Aged ,medicine.disease ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Liver ,Cancer research ,Female ,Steatohepatitis - Abstract
Objective MicroRNAs (miRNAs) are well-known regulators of disease pathogenesis and have great potential as biomarkers and therapeutic targets. We aimed at profiling miRNAs in alcoholic hepatitis (AH) and identifying miRNAs potentially involved in liver injury. Design MiRNA profiling was performed in liver samples from patients with AH, alcohol liver disease, non-alcoholic steatohepatitis, HCV disease and normal liver tissue. Expression of miRNAs was assessed in liver and serum from patients with AH and animal models. Mimic and decoy miR-182 were used in vitro and in vivo to evaluate miR-1829s biological functions. Results MiRNA expression profile in liver was highly altered in AH and distinctive from alcohol-induced cirrhotic livers. Moreover, we identified a set of 18 miRNAs predominantly expressed in AH as compared with other chronic liver conditions. Integrative miRNA-mRNA functional analysis revealed the association of AH-altered miRNAs with nuclear receptors, IGF-1 signalling and cholestasis. Interestingly, miR-182 was the most highly expressed miRNA in AH, which correlated with degree of ductular reaction, disease severity and short-term mortality. MiR-182 mimic induced an upregulation of inflammatory mediators in biliary cells. At experimental level, miR-182 was increased in biliary cells in mice fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet but not upregulated by alcohol intake or fibrosis. Inhibition of miR-182 in DDC-fed mice reduced liver damage, bile acid accumulation and inflammatory response. Conclusions AH is characterised by a deregulated miRNA profile, including miR-182, which is associated with disease severity and liver injury. These results highlight the potential of miRNAs as therapeutic targets and biomarkers in AH.
- Published
- 2016