title: miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis.
abstract: OBJECTIVE
  miRNAs are novel regulators of organ fibrosis. miR-133a plays a role in cardiac and muscle remodeling, but its function in the liver is unclear. We therefore aimed at evaluating a possible function of miR-133a in hepatofibrogenesis.
  
  
  METHODS
  miR-133a levels were measured in whole liver samples from different murine hepatic fibrosis models and human liver tissue from patients with liver cirrhosis. The cell-specific regulation of miR-133a was assessed in FACS-sorted hepatic cell subpopulations. Murine and human primary hepatic stellate cells (HSC) were isolated and treated with different cytokines to evaluate upstream regulators of miR-133a. Moreover, GRX cells were transfected with synthetic miR-133a and the effect on extracellular matrix (ECM) gene regulation was assessed. Finally, miR-133a serum levels were measured in a cohort of patients with chronic liver diseases and correlated with disease progression.
  
  
  RESULTS
  Overall miR-133a expression levels were unchanged in whole RNA extracts from fibrotic murine and human livers. However, miR-133a was specifically downregulated in HSC during fibrogenesis. Treatment of primary murine and human HSC with transforming growth factor (TGF)-β resulted in a significant downregulation of miR-133a in these cells. In turn, overexpression of miR-133a in primary murine HSC led to decreased expression of collagens. In addition, miR-133a serum levels were increased in patients with chronic liver disease and indicated the presence and progression of liver cirrhosis.
  
  
  CONCLUSIONS
  Evidence is presented for a novel antifibrotic functional role of miR-133a in hepatofibrogenesis. miR-133a may thus represent a target for diagnostic and therapeutic strategies in liver fibrosis.
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), 52074 Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.forename: David
authors.initials: D
authors.lastname: Vargas Cardenas
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.forename: Tobias
authors.initials: T
authors.lastname: Mollnow
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016326:Extracellular Matrix Proteins; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen