miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis

J Hepatol. 2013 Apr;58(4):736-42. doi: 10.1016/j.jhep.2012.11.022. Epub 2012 Nov 23.


Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Collagen / biosynthesis*
  • Collagen / genetics
  • Disease Progression
  • Extracellular Matrix Proteins / biosynthesis
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Expression Regulation
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • MicroRNAs / blood
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Middle Aged
  • Transforming Growth Factor beta / metabolism*
  • Young Adult


  • Extracellular Matrix Proteins
  • MIRN133 microRNA, human
  • MicroRNAs
  • Mirn133 microRNA, mouse
  • Transforming Growth Factor beta
  • Collagen