title: Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA.
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.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Nakahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujii
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Maloney
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007668:Kidney; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002635:Chenodeoxycholic Acid; D008156:Luciferases