1. ¹Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China
2. ²Department of Endocrinology and Metabolism, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
3. ³Division of Endocrinology and Metabolism, E-Institutes of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
4. ⁴Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

Correspondence: Professor G Ning, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China. E-mail: guangning@medmail.com.cn

⁵These two authors contributed equally to this work

Received 5 January 2009; Revised 16 April 2009; Accepted 4 May 2009; Published online 1 June 2009.

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 TGF1/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 TGF1/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.