Down-regulation of miR-192-5p protects from oxidative stress-induced acute liver injury.

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.

Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases.

BACKGROUND & AIMS: Serum concentrations of miR-122 were proposed as a marker for various inflammatory diseases, but the mechanisms driving alterations in miR-122 serum levels are unknown. METHODS: We analysed miR-122 serum levels and hepatic miR-122 expression in mice after hepatic ischaemia and reperfusion (I/R) injury. These data were compared with data from mice after caecal pole ligation and puncture (CLP) procedure. To translate these data into the human, we analysed miR-122 serum concentrations in a cohort of 223 patients with critical illness and 57 patients with cirrhosis. RESULTS: We detected strongly elevated levels of miR-122 in mice after hepatic I/R injury. miR-122-concentrations correlated with the degree of liver damage according to AST/ALT and were associated with the presence of hepatic cell death detected by TUNEL staining. miR-122 levels were elevated in the cellular supernatants in an in vitro model of hepatocyte injury, supporting the hypothesis that the passive release of miR-122 represents a surrogate for hepatocyte death in liver injury. Moreover, miR-122 levels were almost normal in patients with cirrhosis without ongoing liver damage, but were elevated when liver injury was present. In contrast to previous assumptions, miR-122-concentrations were independent of the presence of infection/sepsis in mice or human patients. miR-122 levels did not correlate with disease severity or mortality in critically ill patients. In contrast, serum miR-122 levels strictly correlated with the presence of hepatic injury in these patients. CONCLUSION: In mice and humans, miR-122 levels represent an independent and potent marker of ongoing liver injury and hepatic cell death regardless of the underlying disease.

RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation.

For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.