title: Involvement of CETP (Cholesteryl Ester Transfer Protein) in the Shift of Sphingosine-1-Phosphate Among Lipoproteins and in the Modulation of its Functions.
abstract: OBJECTIVE
  Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P.
  
  
  RESULTS
  We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C17S1P bound to apoM-containing lipoprotein, C17S1P and apoM were rapidly transferred to apoB-containing lipoproteins in CETP-overexpressing mice. When HDL containing C17S1P was mixed with low-density lipoprotein ex vivo, C17S1P shifted to the low-density lipoprotein fraction independent of the presence of CETP. Concordant with these results, apoM was distributed mainly to the same fraction as apo AI in a CETP-deficient subject, although apoM was also detected in apo AI-poor fractions in a corresponding hypercholesterolemia subject. About the bioactivities of S1P carried on each lipoprotein, S1P riding on apoB-containing lipoproteins induced the phosphorylation of Akt (AKT8 virus oncogene cellular homolog) and eNOS (endothelial nitric oxide synthase) in human umbilical vein endothelial cells, and CETP overexpression increased insulin secretion and sensitivity, which was inhibited by an S1P receptor 1 or 3 antagonist.
  
  
  CONCLUSIONS
  CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P.
authors.affiliation: From the Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan (M.K., H.I., Y.Y.); Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan (M.H.); and Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Japan (K.T.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurano
authors.affiliation: From the Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan (M.K., H.I., Y.Y.); Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan (M.H.); and Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Japan (K.T.).
authors.forename: Masumi
authors.initials: M
authors.lastname: Hara
authors.affiliation: From the Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan (M.K., H.I., Y.Y.); Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan (M.H.); and Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Japan (K.T.).
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: From the Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan (M.K., H.I., Y.Y.); Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan (M.H.); and Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Japan (K.T.).
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
authors.affiliation: From the Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Japan (M.K., H.I., Y.Y.); Department of Medicine IV, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan (M.H.); and Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Japan (K.T.). yatoyuta-tky@umin.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000097:blood; D001053:Apolipoproteins / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D000075243:Apolipoproteins M; D001646:Bile / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood* / Q000235:genetics; D054834:Lipocalins / Q000097:blood; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D013997:Time Factors; D014162:Transfection
chemical_list: C569471:APOB protein, human; C400523:APOM protein, human; C501623:ApoM protein, mouse; C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001053:Apolipoproteins; D001055:Apolipoproteins B; D000075243:Apolipoproteins M; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D054834:Lipocalins; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: apolipoproteins; hypercholesterolemia; mice; phosphorylation; sphingosine