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Arterioscler Thromb Vasc Biol. 2017 Jun;37(6):1194-1205. doi: 10.1161/ATVBAHA.117.309275. Epub 2017 Apr 6.

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.

Author information

1
From the Division of Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden (C.F., M.R., B.D.); Health Science Center, Department of Medicine, University of Tennessee, Memphis (T.A.H.); and Division of Endocrinology, Metabolism and Diabetes and Diabetes Research Institute, University of Miami Miller School of Medicine, FL (A.J.M., M.C., R.B.G.).
2
From the Division of Clinical Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden (C.F., M.R., B.D.); Health Science Center, Department of Medicine, University of Tennessee, Memphis (T.A.H.); and Division of Endocrinology, Metabolism and Diabetes and Diabetes Research Institute, University of Miami Miller School of Medicine, FL (A.J.M., M.C., R.B.G.). RGoldber@med.miami.edu bjorn.dahlback@med.lu.se.

Abstract

OBJECTIVE:

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.

APPROACH AND RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

apolipoproteins; endothelium; lipoproteins; sphingolipids; tumor necrosis factor-alpha

Comment in

PMID:
28385702
DOI:
10.1161/ATVBAHA.117.309275
[Indexed for MEDLINE]

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