Linked Life Data

16371446

Source:http://linkedlifedata.com/resource/pubmed/id/16371446

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2006-3-22
pubmed:abstractText
Oxysterols are intermediates in the synthesis of bile acids and steroid hormones from cholesterol and function as ligands for liver X receptor (LXR). Bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids and is tightly regulated by its substrates bile acids through nuclear receptor farnesoid X receptor (FXR). In a microarray study using human hepatocytes, BSEP was markedly induced not only by chenodeoxycholic acid (CDCA) but also by oxysterol 22(R)-hydroxycholesterol [22(R)-OHC]. We hypothesized that the expression of BSEP was induced by oxysterols through activation of LXR. To test the hypothesis, human primary hepatocytes or hepatoma cells were treated with 22(R)-OHC, and expression of BSEP was determined. The level of BSEP mRNA was increased as much as 5-fold upon oxysterol induction. In contrast to our hypothesis, the oxysterol-induced up-regulation of BSEP is mediated through FXR but not LXR. BSEP promoter activity was markedly induced by 22(R)-OHC in the presence of FXR but not LXRs. Mutation of the FXR element IR1 in the BSEP promoter significantly reduced its ability to respond to oxysterol induction. To determine whether 22(R)-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. Mutation of residues R331 and I352 abolished activation mediated by CDCA and 22(R)-OHC. In contrast, substitution of residues L340 and R351 differentiated CDCA- and 22(R)-OHC-mediated activation. In conclusion, oxysterol 22(R)-OHC functions as an FXR ligand to induce BSEP expression and differs in the binding with FXR from CDCA.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
317
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
317-25
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16371446-ATP-Binding Cassette Transporters, pubmed-meshheading:16371446-Cell Line, Tumor, pubmed-meshheading:16371446-DNA-Binding Proteins, pubmed-meshheading:16371446-Dose-Response Relationship, Drug, pubmed-meshheading:16371446-Gene Expression, pubmed-meshheading:16371446-Hepatocytes, pubmed-meshheading:16371446-Humans, pubmed-meshheading:16371446-Hydroxycholesterols, pubmed-meshheading:16371446-Mutation, pubmed-meshheading:16371446-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:16371446-Orphan Nuclear Receptors, pubmed-meshheading:16371446-Plasmids, pubmed-meshheading:16371446-Promoter Regions, Genetic, pubmed-meshheading:16371446-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:16371446-Time Factors, pubmed-meshheading:16371446-Transcription Factors, pubmed-meshheading:16371446-Up-Regulation
pubmed:year
2006
pubmed:articleTitle
Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor.
pubmed:affiliation
Department of Biological and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, 02881, USA. dengr@mail.uri.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural