title: Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury.
abstract: miR-192-5p has gained increasing relevance in various diseases, however, its function in acute liver injury is currently unknown. We analysed miR-192-5p serum levels and hepatic miR-192-5p expression in mice after hepatic ischaemia and reperfusion (I/R) as well as in toxic liver injury. On a functional level, miRNA levels were analysed in the different hepatic cell-compartments and in the context of tumour necrosis factor (TNF)-dependent liver cell death. We detected increased serum levels of miR-192-5p after hepatic I/R- and carbon tetrachloride (CCl4)-induced liver injury. miR-192-5p levels correlated with the degree of liver damage and the presence of hepatic cell death detected by TUNEL stainings (terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labelling stainings). Moreover, expression of miR-192-5p was increased in a hypoxia/reoxygenation (H/R) model of in vitro hepatocyte injury, supporting that the passive release of miR-192-5p represents a surrogate for hepatocyte death in liver injury. In critically ill patients, miR-192-5p levels were elevated selectively in patients with liver injury and closely correlated with the presence of hepatic injury. In contrast with up-regulated miR-192-5p in the serum, we detected a down-regulation of miR-192-5p in both injured mouse and human livers. Deregulation of miR-192-5p in livers was dependent on stimulation with TNF. Functional experiments confirmed a protective effect of down-regulation of miR-192-5p in hepatocytes, suggesting a role of miR-192-5p in limiting liver injury. Finally, we identified Zeb2, an important regulator of cell death, as a potential target gene mediating the function of miR-192-5p Our data suggest that miR-192-5p is involved in the regulation of liver cell death during acute liver injury and might represent a potent marker of hepatic injury.
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Sanchari
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Benz
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Alder
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Joern
authors.initials: J
authors.lastname: Janssen
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Schüller
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Loosen
authors.affiliation: Department of Cardiology and Angiology, University of Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany croderburg@ukaachen.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood / Q000502:physiology*; D018384:Oxidative Stress; D012097:Repressor Proteins / Q000502:physiology; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: acute liver failure; critical illness; ischaemia–reperfusion; miR-192-5p; serum