S100A4 promotes liver fibrosis via activation of hepatic stellate cells

J Hepatol. 2015 Jan;62(1):156-64. doi: 10.1016/j.jhep.2014.07.035. Epub 2014 Aug 9.

Abstract

Background & aims: S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs).

Methods: S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA.

Results: S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans.

Conclusions: S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.

Keywords: Activation; Hepatic stellate cells; Liver fibrosis; S100A4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA / genetics*
  • Disease Models, Animal
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation*
  • Hepatic Stellate Cells / pathology
  • Humans
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Polymerase Chain Reaction
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / biosynthesis
  • S100 Proteins / genetics*

Substances

  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • DNA