Delia Blaya1, Mar Coll1, Daniel Rodrigo-Torres1, Maria Vila-Casadesús1, José Altamirano2, Marta Llopis1, Isabel Graupera1, Luis Perea1, Beatriz Aguilar-Bravo1, Alba Díaz3, Jesus M Banales4, Joan Clària5, Juan José Lozano6, Ramon Bataller7, Juan Caballería8, Pere Ginès8, Pau Sancho-Bru1. 1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 2. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 3. Department of Pathology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain. 4. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastian, Spain. 5. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of Biochemistry and Molecular Genetics, Hospital Clínic and Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain. 6. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. 7. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA. 8. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Andressa Franca; Antonio Carlos Melo Lima Filho; Mateus T Guerra; Jittima Weerachayaphorn; Marcone Loiola Dos Santos; Basile Njei; Marie Robert; Cristiano Xavier Lima; Paula Vieira Teixeira Vidigal; Jesus M Banales; Meenakshisundaram Ananthanarayanam; M Fatima Leite; Michael H Nathanson Journal: Hepatology Date: 2018-12-31 Impact factor: 17.425
Authors: Matias A Avila; Jean-François Dufour; Alexander L Gerbes; Fabien Zoulim; Ramon Bataller; Patrizia Burra; Helena Cortez-Pinto; Bin Gao; Ian Gilmore; Philippe Mathurin; Christophe Moreno; Vladimir Poznyak; Bernd Schnabl; Gyongyi Szabo; Maja Thiele; Mark R Thursz Journal: Gut Date: 2019-12-26 Impact factor: 23.059