title: 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.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Cecilia
authors.initials: C
authors.lastname: Frej
authors.affiliation: 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.).
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Mendez
authors.affiliation: 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.).
authors.forename: Mario
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: 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.).
authors.forename: Melanie
authors.initials: M
authors.lastname: Castillo
authors.affiliation: 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.).
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
authors.affiliation: 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.
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlbäck
authors.affiliation: 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.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D001053:Apolipoproteins / Q000097:blood*; D000075243:Apolipoproteins M; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications / Q000175:diagnosis; D019040:E-Selectin / Q000378:metabolism; D004705:Endocytosis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D054834:Lipocalins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D012307:Risk Factors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D000081025:Sphingosine-1-Phosphate Receptors; D053719:Tandem Mass Spectrometry; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D015415:Biomarkers; D019040:E-Selectin; D054834:Lipocalins; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C546936:SELE protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C060506:sphingosine 1-phosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D013110:Sphingosine
keywords: apolipoproteins; endothelium; lipoproteins; sphingolipids; tumor necrosis factor-alpha