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| Content Provider | Journal of Biological Chemistry (JBC) |
|---|---|
| Author | Nakahara, Mayuko Fujii, Hiroshi Maloney, Patrick R. Shimizu, Makoto Sato, Ryuichiro |
| Abstract | 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. |
| Related Links | http://www.jbc.org/content/277/40/37229.abstract |
| Ending Page | 37234 |
| Starting Page | 37229 |
| Page Count | 6 |
| File Format | HTM / HTML PDF |
| ISSN | 00219258 |
| Journal | Journal of Biological Chemistry (JBC) |
| Issue Number | 40 |
| Volume Number | 277 |
| DOI | 10.1074/jbc.M206749200 |
| e-ISSN | 1083351X |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology |
| Publisher Date | 2002-10-04 |
| Access Restriction | Open |
| Subject Keyword | Liver X receptor α (LXRα) Farnesoid X receptor (FXR) Chenodeoxycholic acid (CDCA) Small heterodimer partner (SHP) Low density lipoprotein (LDL) Sterol regulatory element-binding protein (SREBP) Mitogen-activated protein (MAP) Lipoprotein-deficient serum (LPDS) Deoxycholic acid (DCA) Lithocholic acid (LCA) Ursodeoxycholic acid (UDCA) Phorbol 12-myristate 13-acetate (PMA) Fetal bovine serum (FBS) 9-cis-retinoic acid receptor α (RXRα) Intestinal bile acid-binding protein (I-BABP) Extracellular signal-regulated kinase (ERK) Hydroxymethylglutaryl (HMG) Phosphatidylinositol 3kinase (PI3K) Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) Untranslated region (UTR) AU-rich element (ARE) LIPIDS AND LIPOPROTEINS |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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