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Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation
  1. Delia Blaya1,2,
  2. Mar Coll1,2,
  3. Daniel Rodrigo-Torres1,2,
  4. Maria Vila-Casadesús1,2,
  5. José Altamirano1,
  6. Marta Llopis1,2,
  7. Isabel Graupera1,2,
  8. Luis Perea1,2,
  9. Beatriz Aguilar-Bravo1,2,
  10. Alba Díaz3,
  11. Jesus M Banales2,4,
  12. Joan Clària1,5,
  13. Juan José Lozano2,
  14. Ramon Bataller1,6,
  15. Juan Caballería1,2,7,
  16. Pere Ginès1,2,7,
  17. Pau Sancho-Bru1,2
  1. 1Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  2. 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  3. 3Department of Pathology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
  4. 4Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute—Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain
  5. 5Department of Biochemistry and Molecular Genetics, Hospital Clínic and Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain
  6. 6Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA
  7. 7Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
  1. Correspondence to Dr Pau Sancho-Bru, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Roselló, 149-153, third floor, Barcelona 08036, Spain; psancho{at}clinic.ub.es

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-182's 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.

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