Dihydro-sphingosine 1-phosphate interacts with carrier proteins in a manner distinct from that of sphingosine 1-phosphate

Abstract

Dihydro-sphingosine 1-phosphate (DH-S1P) is an analog of sphingosine 1-phosphate (S1P), which is a potent lysophospholipid mediator. DH-S1P has been proposed to exert physiological properties similar to S1P. Although S1P is known to be carried on HDL via apolipoprotein M (apoM), the association between DH-S1P and HDL/apoM has not been fully elucidated. Therefore, in the present study, we aimed to elucidate this association and to compare it with that of S1P and HDL/apoM. First, we investigated the distributions of S1P and DH-S1P among lipoproteins and lipoprotein-depleted fractions in human serum and plasma samples and observed that both S1P and DH-S1P were detected on HDL; furthermore, elevated amounts of DH-S1P in serum samples were distributed to the lipoprotein-depleted fraction to a greater degree than to the HDL fraction. Concordantly, a preference for HDL over albumin was only observed for S1P, and not for DH-S1P, when the molecules were secreted from platelets. Regarding the association with HDL, although both S1P and DH-S1P prefer to bind to HDL, HDL preferentially accepts S1P over DH-S1P. For the association with apoM, S1P was not detected on HDL obtained from apoM knockout mice, while DH-S1P was detected. Moreover, apoM retarded the degradation of S1P, but not of DH-S1P. These results suggest that S1P binds to HDL via apoM, while DH-S1P binds to HDL in a non-specific manner. Thus, DH-S1P is not a mere analog of S1P and might possess unique clinical significance.

Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper‐IgA mice

“…A limitation of this study was that we could not exclude the possibility that the protective effects of ApoM over‐expression in HIGA mice may not be related to the effects of S1P bound to ApoM in the in vivo experiments. As we reported previously (65), the overexpression of ApoM could also increase S1P levels in lipoprotein‐depleted fractions, although S1P contents in HDL fractions were much higher in the ApoM‐overexpressing mice, and complete separation of HDL from lipoprotein‐depleted fractions by ultracentrifugation is difficult. Considering together that S1P contents in HDL were hardly detected in ApoM KO mice (65) and S1P bound to ApoM exerted protective properties in the in vitro experiments, we believe that S1P carried on ApoM/HDL may prevent the progression of the phenotypes of IgA nephropathy in the ApoM‐overexpressing HIGA mice.…”

Modulation of sphingosine 1‐phosphate by hepatobiliary cholesterol handling

“…DhS1P is a similar endogenous analog to S1P, with a similar metabolic pathway also to S1P, except that it is carried on HDL even in the presence of apoM deficiency. 30 The finding that DhS1P was similarly affected by NPC1L1 and ABCG5/8 to S1P in the present study validated the notion that S1P metabolism is modulated by hepatobiliary cholesterol handling.…”

“…The finding that prior treatment of the animals with ezetimibe could block the modulation of S1P metabolism supported the possibility that the transport of cholesterol through NPC1L1 might indirectly affect the transport of S1P, since ezetimibe blocks the cholesterol‐binding part of NPC1L1, 5,32 while the finding that contrary results were not obtained with ABCG5/8 overexpression as compared to the case of NPC1L1 overexpression might support the hypothesis that NPC1L1 directly transports S1P from the bile to hepatocytes, since ABCG5/8 is known to play opposite roles to NPC1L1 in hepatobiliary cholesterol handling. DhS1P is a similar endogenous analog to S1P, with a similar metabolic pathway also to S1P, except that it is carried on HDL even in the presence of apoM deficiency 30 . The finding that DhS1P was similarly affected by NPC1L1 and ABCG5/8 to S1P in the present study validated the notion that S1P metabolism is modulated by hepatobiliary cholesterol handling.…”

“…Although the difference did not reach statistical significance, the biliary S1P levels tended to be lower, and the hepatic dhS1P contents tended to be higher in the L1-KO mice ( Figure 3J and K). As expected from our previous report, 30 we scarcely detected F I G U R E 2 Effects of the HDL separated from the NPC1L1-overexpressing mice treated with or without ezetimibe on the phosphorylation of AKT in HUVECs. We prepare HDL-containing medium from the plasma of WT mice infected with Ad-Null or Ad-L1 which were treated with or without EZ, as described in the Material and method section.…”

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

“…Not surprisingly, liver-specific ApoM overexpression raises the plasma concentration of HDL-ApoM/S1P [164] by eliciting S1P biosynthesis and secretion. In addition, ApoM also protects S1P from degradation, and hence, increases plasma S1P lifespan and activity [223]. It is also thought that ApoM, by delivering S1P to the S1PR1 receptor on endothelial cells, contributes to vascular protection [156].…”