RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 584
OP 595
DO 10.1124/jpet.105.084905
VO 314
IS 2
A1 Stefano Fiorucci
A1 Giovanni Rizzo
A1 Elisabetta Antonelli
A1 Barbara Renga
A1 Andrea Mencarelli
A1 Luisa Riccardi
A1 Stefano Orlandi
A1 Mark Pruzanski
A1 Antonio Morelli
A1 Roberto Pellicciari
YR 2005
UL http://jpet.aspetjournals.org/content/314/2/584.abstract
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