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.

Abstract

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.

• Authors: Stefano Fiorucci, Giovanni Rizzo, Elisabetta Antonelli, Barbara Renga, Andrea Mencarelli, Luisa Riccardi, Stefano Orlandi, Mark Pruzanski, Antonio Morelli, Roberto Pellicciari
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 2 Pg. 584-95 (Aug 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15860571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• DNA-Binding Proteins
• Proto-Oncogene Proteins c-jun
• Receptors, Cytoplasmic and Nuclear
• Tissue Inhibitor of Metalloproteinase-1
• Transcription Factor AP-1
• Transcription Factors
• farnesoid X-activated receptor
• Matrix Metalloproteinases
• Matrix Metalloproteinase 2

Topics

• Actins (metabolism)
• Animals
• Apoptosis (physiology)
• Blotting, Western
• Carbon Tetrachloride Poisoning (pathology)
• Cell Separation
• DNA-Binding Proteins (physiology)
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation (physiology)
• Hepatocytes (enzymology, metabolism)
• Humans
• Immunohistochemistry
• Liver Cirrhosis (chemically induced, metabolism, pathology)
• Matrix Metalloproteinase 2 (biosynthesis)
• Matrix Metalloproteinases (biosynthesis)
• Plasmids (genetics)
• Proto-Oncogene Proteins c-jun (metabolism)
• Rats
• Receptors, Cytoplasmic and Nuclear
• Tissue Inhibitor of Metalloproteinase-1 (biosynthesis)
• Transcription Factor AP-1 (metabolism)
• Transcription Factors (physiology)