Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

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.

Authors: Fiorucci, S  Rizzo, G  Antonelli, E  Renga, B  Mencarelli, A  Riccardi, L  Orlandi, S  Pruzanski, M  Morelli, A  Pellicciari, R 
Citation: Fiorucci S, etal., J Pharmacol Exp Ther. 2005 Aug;314(2):584-95. Epub 2005 Apr 28.
Pubmed: (View Article at PubMed) PMID:15860571
DOI: Full-text: DOI:10.1124/jpet.105.084905

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 CCl(4). Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3-fold and reduces basal and thrombin-stimulated expression of alpha1(I)collagen, alpha-smooth muscle actin (alpha-SMA), TIMP-1, and TIMP-2 by approximately 60 to 70%, whereas it increased matrix metalloprotease (MMP)-2 activity by 2-fold. In coimmunoprecipitation, electromobility 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 CCl(4). In the prevention protocol, 4-week administration of 6-ECDCA reduced alpha1(I)collagen, alpha-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.


Gene Ontology Annotations
Objects Annotated

Additional Information

CRRD Object Information
CRRD ID: 1600916
Created: 2007-03-30
Species: All species
Last Modified: 2007-03-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.