Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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Apoptosis / drug effects
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Carbon Tetrachloride / toxicity
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Proliferation / drug effects
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Collagen / metabolism
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Fibrosis / metabolism
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Fibrosis / pathology
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Hepatic Stellate Cells / drug effects
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Hepatic Stellate Cells / metabolism
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Hepatic Stellate Cells / pathology
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Hepatitis, Viral, Human / metabolism
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Hepatitis, Viral, Human / pathology
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Hepatocytes / drug effects
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Hepatocytes / pathology
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Histone Acetyltransferases / deficiency*
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Humans
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Liver Cirrhosis, Experimental / metabolism
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Liver Cirrhosis, Experimental / pathology
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Liver Cirrhosis, Experimental / prevention & control*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mice
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Mice, Knockout
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Necrosis / chemically induced
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Necrosis / metabolism
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Necrosis / pathology
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Nuclear Receptor Coactivator 3
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Signal Transduction
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Smad2 Protein / metabolism*
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Smad3 Protein / metabolism*
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Tissue Array Analysis
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Trans-Activators / deficiency*
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Transforming Growth Factor beta1 / metabolism*
Substances
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Smad2 Protein
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta1
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Collagen
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Carbon Tetrachloride
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Histone Acetyltransferases
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NCOA3 protein, human
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Ncoa3 protein, mouse
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Nuclear Receptor Coactivator 3