Human Molecular Genetics Advance Access published online on August 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh261
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Research Unit, La Paz University Hospital, Paseo de La Castellana, 261, 28046 Madrid. Spain
* To whom correspondence should be addressed. E-mail: luisalvarez.hulp{at}salud.madrid.org.
Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids, and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and BSEP disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia, and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.
Article
Reduced hepatic expression of Farnesoid X Receptor in hereditary cholestasis associated to mutation in ATP8B1
2 Pediatric Liver Service, La Paz Children's University Hospital
3 Research unit, La Paz University Hospital
4 Department of Pathology, La Paz University Hospital
5 Department of Genetics, La Paz University Hospital
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. M. Kogan, C. Blazquez, L. Alvarez, R. Gallily, M. Schlesinger, M. Guzman, and R. Mechoulam A Cannabinoid Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells Mol. Pharmacol., July 1, 2006; 70(1): 51 - 59. [Abstract] [Full Text] [PDF]
|
|