title: Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment.
abstract: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS).
  
  
  
  Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L-[3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87).
  
  
  
  We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine-1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients.
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.). damien.denimal@chu-dijon.fr.
authors.forename: Damien
authors.initials: D
authors.lastname: Denimal
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Serge
authors.initials: S
authors.lastname: Monier
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Brindisi
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Petit
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bouillet
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Amandine
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Demizieux
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Simoneau
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pais de Barros
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Bruno
authors.initials: B
authors.lastname: Vergès
authors.affiliation: From the University Bourgogne Franche-Comté, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., A.N., L.D., I.S., B.V., L.D.); INSERM, LNC UMR1231, Dijon, France (D.D., S.M., M.-C.B., J.-M.P., B.B., L.D., I.S., J.-P.P.d.B., B.V., L.D.); Department of Biochemistry, University Hospital Dijon-Burgundy, Dijon, France (D.D., L.D.); Department of Endocrinology and Metabolic Diseases, University Hospital Dijon-Burgundy, Dijon, France (M.-C.B., J.-M.P., B.B., A.N., I.S., B.V.); and Lipidomic Analytical Platform, Bâtiment B3, Dijon, France (J.-P.P.d.B.).
authors.forename: Laurence
authors.initials: L
authors.lastname: Duvillard
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000097:blood / Q000175:diagnosis / Q000201:enzymology*; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000175:diagnosis / Q000201:enzymology*; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine
keywords: HDL; eNOS; metabolic syndrome; sphingosine