title: Lysophosphatidylcholine promotes SREBP-2 activation via rapid cholesterol efflux and SREBP-2-independent cytokine release in human endothelial cells.
abstract: Lysophosphatidylcholine (LPC) and oxysterols which are major components in oxidized low-density lipoprotein have been shown to possess an opposite effect on the expression of sterol regulatory element-binding protein-2 (SREBP-2) target genes in endothelial cells. In this study, we aimed at elucidating the mechanisms of activation of SREBP-2 by LPC and evaluating the effects of LPC and 25-hydroxycholesterol (25-HC) on the release of inflammatory cytokines. Human umbilical vein endothelial cells were treated with LPC or oxysterols including 25-HC. LPC activated SREBP-2 within 15 min, resulting in induction of expression of SREBP-2 target genes which were involved in intracellular cholesterol homeostasis. The rapid activation of SREBP-2 was caused by enhanced efflux of intracellular cholesterol, which was evaluated using (14)C-acetate. The LPC-induced activation of SREBP-2 was inhibited by addition of 25-HC. In contrast, both LPC and 25-HC increased release of interleukin-6 (IL-6) and IL-8, respectively and additively. In conclusion, LPC activated SREBP-2 via enhancement of cholesterol efflux, which was suppressed by 25-HC. The release of inflammatory cytokines such as IL-6 and IL-8 in endothelial cells was SREBP-2-independent. LPC and 25-HC may act competitively in cholesterol homeostasis but additively in inflammatory cytokine release.
authors.affiliation: Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan;
authors.forename: Mayuko
authors.initials: M
authors.lastname: Morita
authors.affiliation: Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-0061, Japan;
authors.forename: Azusa
authors.initials: A
authors.lastname: Sekine
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0321, Japan; and.
authors.forename: Yasuomi
authors.initials: Y
authors.lastname: Urano
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Taki
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0321, Japan; and.
authors.forename: Wakako
authors.initials: W
authors.lastname: Takabe
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.affiliation: Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-0061, Japan;
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.affiliation: Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-0061, Japan;
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 610-0321, Japan; and nnoguchi@mail.doshisha.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D021581:Active Transport, Cell Nucleus; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000032:analysis / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000819:agonists / Q000097:blood / Q000378:metabolism*; D016209:Interleukin-8 / Q000819:agonists / Q000097:blood / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000032:analysis / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D010084:Oxidation-Reduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C508606:CXCL8 protein, human; D002250:Carbon Radioisotopes; D006888:Hydroxycholesterols; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C099252:oxidized low density lipoprotein; C007997:25-hydroxycholesterol; D002784:Cholesterol
keywords: 25-hydroxycholesterol; SREBP; cholesterol; cytokine; lysophosphatidylcholine