Loss of steroid receptor co-activator-3 attenuates carbon tetrachloride-induced murine hepatic injury and fibrosis

Lab Invest. 2009 Aug;89(8):903-14. doi: 10.1038/labinvest.2009.51. Epub 2009 Jun 1.


Hepatic fibrosis, a disease characterized by altered accumulation of extracellular matrix, can cause cirrhosis and liver failure. There is growing interest in the impact of co-activators on hepatic fibrogenesis. Here, we provided genetic evidence that mice lacking steroid receptor co-activator-3 (SRC-3) were protected against carbon tetrachloride (CCl4)-induced acute liver necrosis and chronic hepatic fibrosis. After acute CCl4 treatment, SRC-3(-/-) mice showed attenuated profibrotic response and hepatocyte apoptosis, whereas hepatocyte proliferation was elevated in SRC-3(-/-) mice versus SRC-3+/+ mice. Similarly, chronically CCl4-treated SRC-3(-/-) mice showed significant weakening of inflammatory infiltrates, hepatic stellate cell activation and collagen accumulation in the liver compared with SRC-3+/+ mice. Further investigation revealed that TGFbeta1/Smad signaling pathway was impaired in the absence of SRC-3. Moreover, the expression levels of SRC-3, as assessed in human tissue microarray of liver diseases, correlated positively with degrees of fibrosis. These data revealed that SRC-3(-/-) mice were resistant to CCl4-induced acute and chronic hepatic damage and TGFbeta1/Smad signaling was suppressed in the lack of SRC-3. Our results established an essential involvement of SRC-3 in liver fibrogenesis, which might provide new clues to the future treatment of hepatic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Apoptosis / drug effects
  • Carbon Tetrachloride / toxicity
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / drug effects
  • Collagen / metabolism
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Hepatitis, Viral, Human / metabolism
  • Hepatitis, Viral, Human / pathology
  • Hepatocytes / drug effects
  • Hepatocytes / pathology
  • Histone Acetyltransferases / deficiency*
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Necrosis / chemically induced
  • Necrosis / metabolism
  • Necrosis / pathology
  • Nuclear Receptor Coactivator 3
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Tissue Array Analysis
  • Trans-Activators / deficiency*
  • Transforming Growth Factor beta1 / metabolism*


  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta1
  • Collagen
  • Carbon Tetrachloride
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3