A Shift in ApoM/S1P Between HDL-Particles in Women With Type 1 Diabetes Mellitus Is Associated With Impaired Anti-Inflammatory Effects of the ApoM/S1P Complex.

Type 1 diabetes mellitus (T1D) patients have an increased risk of cardiovascular disease despite high levels of high-density lipoproteins (HDL). Apolipoprotein M (apoM) and its ligand sphingosine 1-phospate (S1P) exert many of the anti-inflammatory effects of HDL. We investigated whether apoM and S1P are altered in T1D and whether apoM and S1P are important for HDL functionality in T1D. ApoM and S1P were quantified in plasma from 42 healthy controls and 89 T1D patients. HDL was isolated from plasma and separated into dense, medium-dense, and light HDL by ultracentrifugation. Primary human aortic endothelial cells were challenged with tumor necrosis factor-α in the presence or absence of isolated HDL. Proinflammatory adhesion molecules E-selectin and vascular cellular adhesion molecule-1 were quantified by flow cytometry. Activation of the S1P1- receptor was evaluated by analyzing downstream signaling targets and receptor internalization. There were no differences in plasma levels of apoM and S1P between controls and T1D patients, but the apoM/S1P complexes were shifted from dense to light HDL particles in T1D. ApoM/S1P in light HDL particles from women were less efficient in inhibiting expression of vascular cellular adhesion molecule-1 than apoM/S1P in denser particles. The light HDL particles were unable to activate Akt, whereas all HDL subfractions were equally efficient in activating Erk and receptor internalization. ApoM/S1P in light HDL particles were inefficient in inhibiting tumor necrosis factor-α-induced vascular cellular adhesion molecule-1 expression in contrast to apoM/S1P in denser HDL particles. T1D patients have a higher proportion of light particles and hence more dysfunctional HDL, which could contribute to the increased cardiovascular disease risk associated with T1D.

Frej C ，Mendez AJ ，Ruiz M ，Castillo M ，Hughes TA ，Dahlbäck B ，Goldberg RB ... -  《-》

High-Density Lipoprotein-Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1.

Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both pro- and anti-inflammatory roles have been ascribed to S1P. The goal of this study is to elucidate the role of ApoM and S1P in endothelial anti-inflammatory events related to HDL. Aortic or brain human primary endothelial cells were challenged with tumor necrosis factor-α (TNF-α) as inflammatory stimuli. The presence of recombinant ApoM-bound S1P or ApoM-containing HDL reduced the abundance of adhesion molecules in the cell surface, whereas ApoM and ApoM-lacking HDL did not. Specifically, ApoM-bound S1P decreased vascular adhesion molecule-1 (VCAM-1) and E-selectin surface abundance but not intercellular adhesion molecule-1. Albumin, which is an alternative S1P carrier, was less efficient in inhibiting VCAM-1 than ApoM-bound S1P. The activation of the S1P receptor 1 was sufficient and required to promote anti-inflammation. Moreover, ApoM-bound S1P induced the rearrangement of the expression of S1P-related genes to counteract TNF-α. Functionally, HDL/ApoM/S1P limited monocyte adhesion to the endothelium and maintained endothelial barrier integrity under inflammatory conditions. ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions in the endothelium, including regulation of adhesion molecule abundance, leukocyte-endothelial adhesion, and endothelial barrier.

Ruiz M ，Frej C ，Holmér A ，Guo LJ ，Tran S ，Dahlbäck B ... -  《-》

HDL-associated ApoM is anti-apoptotic by delivering sphingosine 1-phosphate to S1P1 & S1P3 receptors on vascular endothelium.

Ruiz M ，Okada H ，Dahlbäck B 《Lipids in Health and Disease》

Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.

Christoffersen C ，Obinata H ，Kumaraswamy SB ，Galvani S ，Ahnström J ，Sevvana M ，Egerer-Sieber C ，Muller YA ，Hla T ，Nielsen LB ，Dahlbäck B ... -  《-》

Involvement of CETP (Cholesteryl Ester Transfer Protein) in the Shift of Sphingosine-1-Phosphate Among Lipoproteins and in the Modulation of its Functions.

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. 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. CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P.

Kurano M ，Hara M ，Ikeda H ，Tsukamoto K ，Yatomi Y ... -  《-》