Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis
| Autor: | Mary Jo Numerick, Kathleen I. MacKenzie, Bryan Goodwin, Guizhen Luo, Jane G Binz, Yaping Liu, Bhasha Desai, Steven A. Kliewer, Stacey A. Jones, Traci Ann Mansfield, Steve Dennis |
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| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Taurine medicine.drug_class Organic Anion Transporters Sodium-Dependent Receptors Cytoplasmic and Nuclear Naphthalenes Organic Anion Transporters Sodium-Independent Extrahepatic Cholestasis Biology Receptors Tumor Necrosis Factor Liver disorder Rats Sprague-Dawley Cholestasis Internal medicine medicine Animals Steroid 12-alpha-Hydroxylase Symporters Bile acid Ursodeoxycholic Acid Membrane Transport Proteins Isoxazoles General Medicine medicine.disease G protein-coupled bile acid receptor Bile duct proliferation Ursodeoxycholic acid Rats DNA-Binding Proteins Receptors TNF-Related Apoptosis-Inducing Ligand Endocrinology Cytoprotection ATP-Binding Cassette Transporters Farnesoid X receptor Carrier Proteins Isocyanates Transcription Factors medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 112:1678-1687 |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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