Die Modulation der humanen und murinen Leberfibrose durch die miRNA-29-Familie

MiRNAs are small noncoding RNAs, that negatively regulate genexpression by affecting translation and transcription of proteins, in virtually all cell processes. Even in the complex network of hepatic fibrogenesis and hepatocarcinogenesis they seem to play a crutial role. We analyzed expression profiles of miRNAs in the murin, carbon tetrachloride-induced (CCl4) model of liver fibrosis by gene array analysis. All three members of the MiRNA-29-family occured to be significantly down-regulated. The bile-duct-ligation model revealed the same results as well. Additional to these findings, patients suffering advanced liver cirrhosis showed lower miRNA-29-expression in hepatic tissue. Compared to healthy controls or patients with early fibrosis, serum levels of miRNA-29 in advanced cirrhosis were decreased. In cell culture inflamatory signals, such as transforming growth factor beta (TGF-β), lipopolysaccharide (LPS) and nuclear factor kappa B (NF-κB) were responsible for down-regulation of miR-29 in murine hepatic stellate cells (HSCs), resulting in a stronger collagen expression. MiRNA-29b-overexpression reversely mediated a down-regulation of collagen expression in murin HSC. Conclusion: The miRNA-29-family is part of a signaling network that controlls fibrogenesis. Its down-regulation mediated by inflamatory signals, e.g. transforming growth factor beta (TGF-β), lipopolysaccharide (LPS) and nuclear factor kappa B (NF-κB), results in up-regulation of extracellular matrix genes in HSC. This may contribute to develop new therapeutic approaches and biomarkers for diagnosis and surveillance of liver fibrosis