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

Makoto Kurano,Kazuhisa Tsukamoto,Masumi Hara,Ryunosuke Ohkawa,Hitoshi Ikeda,Yutaka Yatomi

doi:10.1074/jbc.m114.596445

Abstract

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.

Highlights

A positive correlation exists between sphingosine 1-phosphate (S1P) and LDL cholesterol
S1P is known to bind mainly to HDL, we have reported that in human subjects, the plasma S1P level is positively correlated with the levels of LDL cholesterol, triglycerides, apolipoprotein B, apolipoprotein C-II, and apolipoprotein C-III as well as the red blood cell (RBC) count and the albumin level, but the plasma S1P level is not significantly correlated with the HDL cholesterol or apolipoprotein A-I levels [17]
In view of the results from these reports, the LDL receptor might clear S1P as well as apolipoprotein M (apoM)-containing lipoproteins; if the LDL receptor clears S1P bound to apoM-containing lipoproteins, it is rational that plasma S1P levels are correlated with LDL cholesterol, because LDL receptor is established to clear LDL, and S1P and LDL cholesterol undergo clearance through the same protein, LDL receptor

Summary

Background

A positive correlation exists between sphingosine 1-phosphate (S1P) and LDL cholesterol. In the field of vascular biology, S1P has important roles because of its anti-atherosclerotic properties, such as anti-apoptosis [7], anti-inflammation [8, 9], vasorelaxation through the induction of eNOS [10, 11], and the preservation of vascular permeability [12,13,14] In agreement with these basic studies, the plasma S1P level and the HDL-linked S1P level have been shown to be reduced in subjects with coronary artery diseases [15, 16]. When we utilized the apolipoprotein level instead of LDL cholesterol, HDL cholesterol, and TG levels, apoB (and not apoA-I) was selected as a significant explanatory factor (Table 1) These results suggest the possibility that the metabolic pathway involved in the clearance of LDL, such as LDL receptor, might have some roles in the clearance of S1P

The abbreviations used are

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION