RGD Reference Report - Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. - Rat Genome Database

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Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.

Authors: Liu, Y  Binz, J  Numerick, MJ  Dennis, S  Luo, G  Desai, B  MacKenzie, KI  Mansfield, TA  Kliewer, SA  Goodwin, B  Jones, SA 
Citation: Liu Y, etal., J Clin Invest. 2003 Dec;112(11):1678-87. Epub 2003 Nov 17.
RGD ID: 1625205
Pubmed: PMID:14623915   (View Abstract at PubMed)
PMCID: PMC281645   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI18945   (Journal Full-text)

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NR1H4Humanextrahepatic cholestasis  ISONr1h4 (Rattus norvegicus) RGD 
Nr1h4Ratextrahepatic cholestasis  IDA  RGD 
Nr1h4Mouseextrahepatic cholestasis  ISONr1h4 (Rattus norvegicus) RGD 

Objects Annotated

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

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

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


Additional Information