RGD Reference Report - Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. - Rat Genome Database

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Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis.

Authors: Fiorucci, S  Rizzo, G  Antonelli, E  Renga, B  Mencarelli, A  Riccardi, L  Morelli, A  Pruzanski, M  Pellicciari, R 
Citation: Fiorucci S, etal., J Pharmacol Exp Ther. 2005 Oct;315(1):58-68. Epub 2005 Jun 24.
RGD ID: 1625201
Pubmed: PMID:15980055   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.105.085597   (Journal Full-text)

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPARgamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPARgamma mRNA by approximately 40-fold. Submaximally effective concentrations of FXR and PPARgamma ligands were additive in inhibiting alpha1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARgamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARgamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGFbeta1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARgamma and uncoupling protein 2, a PPARgamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARgamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARgamma cascade exerts counter-regulatory effects in HSCs activation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Liver Cirrhosis treatmentISOFn1 (Rattus norvegicus)1625201; 1625201mRNA:altered expression:liver (rat)RGD 
Experimental Liver Cirrhosis treatmentIMP 1625201; 1625201mRNA:altered expression:liver (rat)RGD 
Experimental Liver Cirrhosis treatmentISONr1h4 (Rattus norvegicus)1625201; 1625201mRNA:altered expression:liver (rat)RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
chenodeoxycholic acid increases expressionISONr1h4 (Rattus norvegicus)1625201; 1625201chenodeoxycholic acid increases expression of Nr1H4 mRNA in rat hepatic stellate cellsRGD 
chenodeoxycholic acid increases expressionEXP 1625201chenodeoxycholic acid increases expression of Nr1H4 mRNA in rat hepatic stellate cellsRGD 
GW 4064 increases expressionISONr1h4 (Rattus norvegicus)1625201; 1625201GW4064 increases expression of Nr1H4 mRNA in rat hepatic stellate cellsRGD 
GW 4064 increases expressionEXP 1625201GW4064 increases expression of Nr1H4 mRNA in rat hepatic stellate cellsRGD 
obeticholic acid decreases expressionISOFn1 (Rattus norvegicus)1625201; 1625201obeticholic acid decreases expression of fibronectin mRNA in liver in porcine serum induced model of cirrhosis in ratRGD 
obeticholic acid decreases expressionEXP 1625201obeticholic acid decreases expression of fibronectin mRNA in liver in porcine serum induced model of cirrhosis in ratRGD 
obeticholic acid increases expressionISONr1h4 (Rattus norvegicus)1625201; 1625201obeticholic acid increases expression of Nr1H4 mRNA in rat hepatic stellate cells and obeticholic acid increases expression of Nr1h4 mRNA in bile duct ligation and porcine serum induced models of cirrhosis in ratRGD 
obeticholic acid increases expressionEXP 1625201obeticholic acid increases expression of Nr1H4 mRNA in rat hepatic stellate cells and obeticholic acid increases expression of Nr1h4 mRNA in bile duct ligation and porcine serum induced models of cirrhosis in ratRGD 
rosiglitazone decreases expressionISOFn1 (Rattus norvegicus)1625201; 1625201rosiglitazone decreases expression of fibronectin mRNA in liver in porcine serum induced model of cirrhosis in ratRGD 
rosiglitazone decreases expressionEXP 1625201rosiglitazone decreases expression of fibronectin mRNA in liver in porcine serum induced model of cirrhosis in ratRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of collagen biosynthetic process  IMP 1625201; 1625201 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
liver fibrosis  IDA 1625201 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Fn1  (fibronectin 1)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)

Genes (Mus musculus)
Fn1  (fibronectin 1)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)

Genes (Homo sapiens)
FN1  (fibronectin 1)
NR1H4  (nuclear receptor subfamily 1 group H member 4)


Additional Information