LDL Receptor and ApoE Are Involved in the Clearance of ApoM-associated Sphingosine 1-Phosphate

• Published in: The Journal of biological chemistry Vol. 290; no. 4; pp. 2477 - 2488
• Main Authors: Kurano, Makoto, Tsukamoto, Kazuhisa, Hara, Masumi, Ohkawa, Ryunosuke, Ikeda, Hitoshi, Yatomi, Yutaka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apolipoprotein; Apolipoprotein E (ApoE); Apolipoproteins - metabolism; Apolipoproteins E - metabolism; Apolipoproteins M; Cholesterol - blood; Cholesterol, HDL - metabolism; DNA, Complementary - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hep G2 Cells; Humans; Ligands; Lipids; Lipoprotein Receptor; Liver - metabolism; Low-density Lipoprotein (LDL); Lysophospholipids - blood; Mice; Mice, Inbred C57BL; Receptors, LDL - metabolism; Regression Analysis; Sphingosine - analogs & derivatives; Sphingosine - blood; Sphingosine 1-Phosphate (S1P); Apolipoprotein E (ApoE); Apolipoprotein; Lipoprotein Receptor; Sphingosine 1-Phosphate (S1P); Low-density Lipoprotein (LDL)
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.596445

Sphingosine 1-phosphate (S1P) is a vasoactive lipid mediator that is speculated to be involved in various aspects of atherosclerosis. About 70% of circulating plasma S1P is carried on HDL, and several pleiotropic properties of HDL have been ascribed to S1P. In the previous study with human subjects, however, LDL cholesterol or apoB, but not HDL cholesterol or apoA-I, had a significant positive correlation with the plasma S1P level, suggesting that the metabolic pathway for LDL might have some roles in the metabolism of S1P. In this study, we analyzed the association between LDL receptor, an important protein in the clearance of LDL, and circulating S1P. We observed that in LDL receptor-overexpressing mice, the plasma S1P levels as well as apolipoprotein M (apoM), a carrier of S1P, were decreased and that exogenously administered C17S1P bound to apoM-containing lipoproteins was cleared more rapidly. Unlike the situation in wild-type mice, LDL receptor overexpression in apoE-deficient mice did not reduce the plasma S1P or apoM levels, suggesting that apoE might be a ligand for the LDL receptor during the clearance of these factors. The present findings clarify the novel roles of the LDL receptor and apoE in the clearance of S1P, a multifunctional bioactive phospholipid.A positive correlation exists between sphingosine 1-phosphate (S1P) and LDL cholesterol. Hepatic LDL receptor overexpression decreased plasma S1P together with apoM in wild-type mice, but not in apoE-deficient mice. LDL receptor is involved in the clearance of S1P, utilizing apoE as a ligand. We propose the novel role of LDL receptor and apoE in the clearance of S1P.