Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.
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.
Liu
Yaping
Y
Nuclear Receptor Functional Analysis, High Thruput Biology, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
Binz
Jane
J
Numerick
Mary Jo
MJ
Dennis
Steve
S
Luo
Guizhen
G
Desai
Bhasha
B
MacKenzie
Kathleen I
KI
Mansfield
Traci A
TA
Kliewer
Steven A
SA
Goodwin
Bryan
B
Jones
Stacey A
SA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology*; D017953:Isocyanates / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D026901:Membrane Transport Proteins; D009281:Naphthalenes / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics; D027981:Symporters; D013654:Taurine / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D017953:Isocyanates; D007555:Isoxazoles; D026901:Membrane Transport Proteins; D009281:Naphthalenes; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D018160:Receptors, Cytoplasmic and Nuclear; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D013253:Steroid 12-alpha-Hydroxylase; D027981:Symporters; D013654:Taurine; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C421102:Slco1a1 protein, rat; C505644:Tnfrsf10b protein, rat; C030141:taurine-ursodeoxycholate conjugate; C071908:sodium-bile acid cotransporter; C061621:alpha-naphthyl isocyanate; C095122:multidrug resistance protein 3; C412815:GW 4064