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

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 SIP level, suggesting that the metabolic pathway for LDL might have some roles in the metabolism of SIP. In this study, we analyzed the association between LDL, receptor, an important protein in the clearance of LDL, and circulating SIP. We observed that in LDL, receptor-overexpressing mice, the plasma SIP levels as well as apolipoprotein M (apoM), a carrier of SIP, were decreased and that exogenously administered C(17)S1P 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 SIP 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 apoL in the clearance of S1P, a multifunctional bioactive phospholipid.