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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 28, 2005; DOI: 10.1124/jpet.105.084905

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Received for publication February 14, 2005.
Revised April 27, 2005.
Accepted for publication April 27, 2005.

A FXR-SHP Regulatory Cascade Modulates TIMP-1 and MMPs Expression in HSCs and Promotes Resolution of Liver Fibrosis

Stefano Fiorucci 1*, Giovanni Rizzo 1, Elisabetta Antonelli 1, Barbara Renga 1, Andrea Mencarelli 1, Luisa Riccardi 1, Stefano Orlandi 1, Mark Pruzanski 2, Antonio Morelli 1, Roberto Pellicciari 1

1 University of Perugia 2 Intercept Pharmaceuticals

* Address correspondence to: E-mail: fiorucci{at}unipg.it

Abstract

The farnesoid X receptor (FXR) is expressed by and regulates hepatic stellate cells (HSCs). In the present study we investigated whether 6-ethyl chenodeoxyxholic acid (6-ECDCA or INT-747), a semi- synthetic derivative of CDCA, modulates tissue metalloproteinase inhibitor (TIMP)-1 and matrix metalloprotease (MMP)-2 expression/activity in HSCs and in the liver of rats rendered cirrhotic by 4-week administration of carbon tetrachloride ((CCl4). Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3 fold and reduces basal and thrombin-stimulated expression of {alpha}1(I)collagen, {alpha}-SMA, TIMP-1 and TIMP-2 by 60-70%, while increased matrix metalloprotease (MMP)-2 activity by 2 folds. In co- immunoprecipitation, electro-mobility shift and transactivation experiments FXR activation/overexpression caused a SHP-dependent inhibition of JunD binding to its consensus element in the TIMP-1 promoter. Inhibition of TIMP-1 expression by SHP overexpression enhanced the sensitivity of HSCs to pro-apoptogenic stimuli. Administration of 6- ECDCA, 3 mg/kg, but not ursodeoxycholic acid, 15 mg/kg, resulted in early (3-5 days) induction of SHP and prevention of early upregulation of TIMP-1 mRNA induced by CCl4. In the prevention protocol, 4 weeks administration of 6-ECDCA reduced {alpha}1(I) collagen, {alpha}-SMA and TIMP-1 mRNA by 60-80% while increased MMP-2 activity by 5 folds. In the resolution protocol, administration of 6-ECDCA (3 mg/kg) promoted liver fibrosis resolution and increased the apoptosis of non-parenchyma liver cells. By demonstrating that a FXR-SHP regulatory cascade promotes the development of a quiescent phenotype and increases apoptosis of HSCs, this study establishes that FXR ligands may be beneficial in treatment of liver fibrosis.


Key words: FXR, Hepatic stellate cells, Liver fibrosis, Nuclear receptors, TIMP-1, alfa 1-collagen


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