Makoto Kurano1, Masumi Hara1, Hitoshi Ikeda1, Kazuhisa Tsukamoto1, Yutaka Yatomi2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Elena M G Diarte-Añazco; Karen Alejandra Méndez-Lara; Antonio Pérez; Núria Alonso; Francisco Blanco-Vaca; Josep Julve Journal: Int J Mol Sci Date: 2019-12-12 Impact factor: 5.923
Authors: Amarylis C B A Wanschel; Daniele M Guizoni; Estela Lorza-Gil; Alessandro G Salerno; Adriene A Paiva; Gabriel G Dorighello; Ana Paula Davel; Wayne Balkan; Joshua M Hare; Helena C F Oliveira Journal: Biomolecules Date: 2021-01-07
Authors: María Concepción Izquierdo; Niroshan Shanmugarajah; Samuel X Lee; Michael J Kraakman; Marit Westerterp; Takumi Kitamoto; Michael Harris; Joshua R Cook; Galina A Gusarova; Kendra Zhong; Elijah Marbuary; InSug O-Sullivan; Nikolaus Rasmus; Stefania Camastra; Terry G Unterman; Ele Ferrannini; Barry E Hurwitz; Rebecca A Haeusler Journal: J Clin Invest Date: 2022-04-01 Impact factor: 19.456