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J. Biol. Chem., Vol. 277, Issue 40, 37229-37234, October 4, 2002
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From the Department of Applied Biological Chemistry, Graduate
School of Agricultural and Life Sciences, The University of Tokyo,
Tokyo 113-8657, Recent studies have indicated that bile acids
regulate the expression of several genes involved in bile acid and
lipid metabolism as ligands for the farnesoid X receptor (FXR). We
report here that bile acids are directly able to govern cholesterol
metabolism by a novel mechanism. We show that chenodeoxycholic acid
(CDCA) enhances low density lipoprotein (LDL) receptor gene expression in human cultured cell lines (HeLa, Hep G2, and Caco-2). The
proteolytic activation of sterol regulatory element-binding protein-2
(SREBP-2), a major regulator for LDL receptor gene expression, is not
affected by CDCA. Both deoxycholic acid and lithocholic acid as well as CDCA, but not ursodeoxycholic acid, increase the mRNA level for the
LDL receptor, even when Hep G2 cells are cultured with
25-hydroxycholesterol, a potent suppressor of gene expression for the
LDL receptor. Although it seems possible that FXR might be involved in
genetic regulation, both reporter assays with a reporter gene
containing the LDL receptor promoter as well as Northern blot analysis
reveal that FXR is not involved in the process. On the other hand,
inhibition of mitogen-activated protein (MAP) kinase activities, which
are found to be induced by CDCA, abolishes the CDCA-mediated
up-regulation of LDL receptor gene expression. We further demonstrate
that CDCA stabilizes LDL receptor mRNA and that the MAP kinase
inhibitors accelerate its turnover. Taken together, these
results indicate that bile acids increase LDL uptake and the
intracellular cholesterol levels through the activation of MAP kinase
cascades in conjunction with a down-regulation of bile acid
biosynthesis by FXR. This work opens up a new avenue for developing
pharmaceutical interventions that lower plasma LDL by stabilizing LDL
receptor mRNA.
Bile Acids Enhance Low Density Lipoprotein Receptor Gene
Expression via a MAPK Cascade-mediated Stabilization of mRNA*
, Department of Signal Transduction
Research, Niigata University, Graduate School of Medicine and Dental
Sciences, Niigata 951-8510, Japan, and § Nuclear Receptor
Discovery Research, GlaxoSmithKline,
Research Triangle Park, North Carolina 27709
*
This work was supported by research grants from the Ministry
of Education, Science, Sports, and Culture of Japan.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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