The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.
OBJECTIVE
The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits bile acid synthesis by inducing small heterodimer partner (SHP) gene expression. The aim of this study was to investigate whether FXR is expressed by and modulates function of hepatic stellate cells (HSCs).


METHODS
The antifibrotic activity of FXR ligand was tested in 2 rodent models: the porcine serum and bile duct ligation (BDL).


RESULTS
Twelve-week administration of 1-10 mg/kg 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic FXR ligand, to porcine serum-treated rats prevented liver fibrosis development and reduced liver expression of alpha1(I) collagen, TGF-beta1 and alpha-SMA mRNA by approximately 90%. Therapeutic administration of 6-ECDCA, 3 mg/kg, to BDL rats reduced liver fibrosis and alpha1(I) collagen, transforming growth factor (TGF)-beta1, alpha-SMA, and tissue metalloproteinase inhibitor (TIMP)-1 and 2 messenger RNA (mRNA) by 70%-80%. No protection was observed in BDL rats treated with CDCA, 3 mg/kg, and ursodeoxycholic acid, 15 mg/kg. FXR expression was detected in HSCs. Exposure of HSCs to FXR ligands caused a 3-fold increase of SHP, reduced alpha1(I)collagen and TGF-beta1 by approximately 60%-70% and abrogates alpha1(I) collagen mRNA up-regulation induced by thrombin and TGF-beta1. By retrovirus infection and small interference RNA, we generated SHP overexpressing and SHP-deficient HSC-T6. Using these cell lines, we demonstrated that SHP binds JunD and inhibits DNA binding of adaptor protein (AP)-1 induced by thrombin.


CONCLUSIONS
By demonstrating that an FXR-SHP regulatory cascade promotes resolution of liver fibrosis, this study establish that FXR ligands might represent a novel therapeutic option to treat liver fibrosis.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Endoscopia Digestiva, Perugia, Italy. fiorucci@unipg.it
Antonelli
Elisabetta
E
Rizzo
Giovanni
G
Renga
Barbara
B
Mencarelli
Andrea
A
Riccardi
Luisa
L
Orlandi
Stefano
S
Pellicciari
Roberto
R
Morelli
Antonio
A
D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006909:Hydroxyproline / Q000378:metabolism / Q000652:urine; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D013552:Swine; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D006909:Hydroxyproline; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C464660:obeticholic acid