Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis.
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-β) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF-κB). Furthermore, overexpression of miR-29b in murine HSC resulted in down-regulation of collagen expression.


CONCLUSIONS
Our data indicate that miR-29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF-β- and NF-κB-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.
Roderburg
Christoph
C
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Urban
Gerd-Willem
GW
Bettermann
Kira
K
Vucur
Mihael
M
Zimmermann
Henning
H
Schmidt
Sabine
S
Janssen
Jörn
J
Koppe
Christiane
C
Knolle
Percy
P
Castoldi
Mirco
M
Tacke
Frank
F
Trautwein
Christian
C
Luedde
Tom
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001652:Bile Ducts / Q000502:physiology; D002252:Carbon Tetrachloride Poisoning / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D008070:Lipopolysaccharides; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016212:Transforming Growth Factor beta