Regulatory effeots of FXR activationon expression of TIMP-1,&nbsp; TIMP-2 and MMP-2&nbsp; in&nbsp; hepatic stellate cells

Chen KeQuan; Zhou BiYao; Chen YaYing; Zou YuanFang; Zhou Yu

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Apr. 2013

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Article Navigation > Journal of Clinical Hepatology > 2013 > 29(4): 290-293

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Regulatory effeots of FXR activationon expression of TIMP-1, TIMP-2 and MMP-2 in hepatic stellate cells

Published Date: 2013-04-20

Abstract

Abstract

Objective To determine whether the regulator of bile acid and carbohydrate metabolism in hepatic stellate cells (HSCs) , Farnesoid X receptor (FXR) , mediates the expression of fibrosis-related genes tissue inhibitor of matrix metalloproteinase (TIMP) -1, TIMP-2, and matrix metalloproteinase-2 (MMP-2) .Methods An in vitro cell culture system with the rat HSC-T6 line was used to evaluate the effects of FXR by treating with the synthetic FXR agonist GW4064 at various concentrations (0.01, 0.1 and 1 μmol/L) for 18 h.Untreated cells served as controls.The mRNA levels of FXR, TIMP-1, TIMP-2, and MMP-2 were measured by real-time reverse transcription PCR.The protein levels of TIMP-1, TIMP-2, and MMP-2 were determined by western blotting.The significance of intergroup differences was assessed by single-factor one-way ANOVA statistical analysis.Results Treatment with GW4064 led to significantly increased mRNA expression of FXR (0.01 μmol/L vs.control, P<0.01) .While the 0.1 μmol/L concentration of GW4064 stimulated a significantly higher level of FXR mRNA expression than the 0.01 μmol/L concentration (P<0.01) 1="" the="" level="" was="" not="" significantly="" different="" from="" that="" stimulated="" by="" l="" concentration="" p="">0.05) .Unlike the 0.01 μmol/L concentration of GW4064, the 0.1 and 1 μmol/L concentrations reduced the TIMP-1 and TIMP-2 mRNA and protein expressions to levels significantly lower than that in the controls (all P<0.05) .GW4064 treatment increased MMP-2 mRNA and protein expressions and the 1 μmol/L mediated increase was significantly higher than that of the control (P<0.01) .Conclusion Activation of FXR on HSCs may contribute to fibrosis by down-regulating TIMP-1 and TIMP-2 and up-regulating MMP-2, which mediate the balance of extracellular matrix synthesis and degradation;thus, FXR ligands may represent useful therapeutic targets of liver fibrosis.
- astrocytes,
- hepatocytes,
- liver cirrhosis,
- matrix metalloproteinases

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Regulatory effeots of FXR activationon expression of TIMP-1, TIMP-2 and MMP-2 in hepatic stellate cells

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Regulatory effeots of FXR activationon expression of TIMP-1, TIMP-2 and MMP-2 in hepatic stellate cells

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