Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor

被引:70
作者
Anisfeld, AM
Kast-Woelbern, HR
Meyer, ME
Jones, SA
Zhang, YQ
Williams, KJ
Willson, T
Edwards, PA
机构
[1] Univ Calif Los Angeles, Dept Med & Biol Chem, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[3] GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA
[4] Thomas Jefferson Univ, Dept Med, Div Endocrinol Diabet & Metab Dis, Dorrance H Hamilton Res Labs, Philadelphia, PA 19107 USA
关键词
D O I
10.1074/jbc.M302505200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that participates in the binding and internalization of extracellular ligands, was identified in a screen designed to isolate genes that are regulated by the farnesoid X-receptor (FXR, NR1H4). Treatment of human hepatocytes with either naturally occurring ( chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein. Transient transfection assays, using wild-type and mutant SDC1 promoter-luciferase genes, led to the identification of a nuclear hormone receptor-binding hexad arranged as a direct repeat separated by one nucleotide (DR-1) in the proximal promoter that was necessary and sufficient for activation by FXR. The wild-type, but not a mutated DR-1 element, conferred FXR responsiveness to a heterologous thymidine kinase promoter-reporter gene. Four murine FXR isoforms have been identified recently that differ either at their amino terminus and/or by the presence or absence of four amino acids in the hinge region. Interestingly, the activities of the human SDC1 promoter-reporter constructs were highly induced by the two FXR isoforms that do not contain the four-amino acid insert and were unresponsive to the isoforms containing the four amino acids. Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner. Increased expression of SDC1 may account in part for the hypotriglyceridemic effect that can result from the administration of chenodeoxycholic acid to humans.
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页码:20420 / 20428
页数:9
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