PT  - JOURNAL ARTICLE
AU  - Fiorucci, Stefano
AU  - Rizzo, Giovanni
AU  - Antonelli, Elisabetta
AU  - Renga, Barbara
AU  - Mencarelli, Andrea
AU  - Riccardi, Luisa
AU  - Orlandi, Stefano
AU  - Pruzanski, Mark
AU  - Morelli, Antonio
AU  - Pellicciari, Roberto
TI  - A Farnesoid X Receptor-Small Heterodimer Partner Regulatory Cascade Modulates Tissue Metalloproteinase Inhibitor-1 and Matrix Metalloprotease Expression in Hepatic Stellate Cells and Promotes Resolution of Liver Fibrosis
AID  - 10.1124/jpet.105.084905
DP  - 2005 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 584--595
VI  - 314
IP  - 2
4099  - http://jpet.aspetjournals.org/content/314/2/584.short
4100  - http://jpet.aspetjournals.org/content/314/2/584.full
SO  - J Pharmacol Exp Ther2005 Aug 01; 314
AB  - The farnesoid X receptor (FXR) is expressed by and regulates hepatic stellate cells (HSCs). In the present study, we investigated whether 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic derivative of chenodeoxycholic acid (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 CCl4. Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3-fold and reduces basal and thrombin-stimulated expression of α1(I)collagen, α-smooth muscle actin (α-SMA), TIMP-1, and TIMP-2 by ≈60 to 70%, whereas it increased matrix metalloprotease (MMP)-2 activity by 2-fold. In coimmunoprecipitation, 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 proapoptogenic stimuli. Administration of 3 mg/kg 6-ECDCA, but not 15 mg/kg ursodeoxycholic acid, resulted in early (3–5-day) induction of SHP and prevention of early up-regulation of TIMP-1 mRNA induced by CCl4. In the prevention protocol, 4-week administration of 6-ECDCA reducedα 1(I)collagen, α-SMA, and TIMP-1 mRNA by 60 to 80%, whereas it increased MMP-2 activity by 5-fold. In the resolution protocol, administration of 3 mg/kg 6-ECDCA promoted liver fibrosis resolution and increased the apoptosis of nonparenchyma 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. The American Society for Pharmacology and Experimental Therapeutics