Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis

Abstract

Liver fibrosis is orchestrated by a complex network of signaling pathways regulating the deposition of extracellular matrix proteins during fibrogenesis. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. Recently, miRNAs have been suggested to crucially modulate cellular processes in the liver such as hepatocarcinogenesis. However, their role in liver fibrosis is not well understood. We systematically analyzed the regulation of miRNAs in a mouse model of carbon tetrachloride-induced hepatic fibrogenesis (CCl 4) by gene array analysis, which revealed a panel of miRNA that were specifically regulated in livers of mice undergoing hepatic fibrosis. Within those, all three members of the miR-29-family were significantly down-regulated in livers of CCl 4-treated mice as well as in mice that underwent bile duct ligation. Specific regulation of miR-29 members in murine fibrosis models correlated with lower expression of miR-29 in livers from patients with advanced liver fibrosis. Moreover, patients with advanced liver cirrhosis showed significantly lower levels of miR-29a in their serum when compared with healthy controls or patients with early fibrosis. On a cellular level, down-regulation of miR-29 in murine hepatic stellate cells (HSCs) was mediated by transforming growth factor beta (TGF-b) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF-jB). Furthermore, overexpression of miR-29b in murine HSC resulted in down-regulation of collagen expression. Conclusion: Our data indicate that miR-29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF-band NF-jB-dependent down-regulation of miR-29 family members in HSC with subsequent up-regulation of extracellular matrix genes. Thus they may represent targets for novel therapeutic strategies against hepatic fibrogenesis and also might evolve as biomarkers in the diagnosis of liver fibrosis.

Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29

“…Similarly, Ogawa et al 29 demonstrated that miR-29 inhibits the production of fibrillar collagen in HSC, suggesting also a function of miR-29 in liver fibrosis. 26 In the present study, we provide detailed evidence for the antifibrotic action of miR-29 interfering with the profibrotic growth factor release from HSC, pointing to its central role in chronic liver disease. Our data demonstrate that miR-29 represses not only fibrotic accumulation of collagen I, III, and IV as previously shown, [26][27][28][29][30] but also expression of profibrogenic mediators, platelet-derived growth factor C (PDGF-C) and insulin-like growth factor I (IGF-I) in HSC.…”

“…24,25 In particular, members of the miR-29 family, repressed during myofibroblastic activation, 26 are of special interest, because their dysregulation has been shown to be involved in synthesis of ECM proteins. [26][27][28][29][30] The miR-29 family consists of miR-29a, miR-29b, and miR-29c, differing only in two or three bases. The miR-29a and miR-29b 1 , as well as miR-29c and miR-29b 2 , are encoded and transcribed in tandem by two genes located on chromosome 7 or chromosome 1, respectively.…”

miRNA Control of Tissue Repair and Regeneration

“…Dysregulation of ECM caused by lower miR-29 is associated with fibrosis development in several organs, including the heart, 77 kidney, 79 lung, 80 and liver. 81 Furthermore, miR-29 influences tissue differentiation and senescence. 82 Elevated expression of miR-29 may mitigate the inhibitory effect of transforming growth factor-b on myogenesis by targeting histone deacetylase 4, a key inhibitor of muscle differentiation.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…139 MiR29b may be a novel regulator of type I collagen expression. 140 MiR-29 families are shown to be very important regulators of liver fibrosis and could serve as potential biomarker for advanced cirrhosis.…”