Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities.
OBJECTIVE
The purpose of this study was to define heterogeneity in the molecular profile of lipids, including sphingomyelin and sphingosine-1-phosphate, among physicochemically-defined HDL subpopulations and potential relevance to antiatherogenic biological activities of dense HDL3.


RESULTS
The molecular profile of lipids (cholesteryl esters, phospholipids, sphingomyelin, and sphingosine-1-phosphate) in physicochemically-defined normolipidemic HDL subpopulations was determined by high-performance liquid chromatography and gas chromatography. As HDL particle size and molecular weight decreased with increment in density, molar lipid content diminished concomitantly. On a % basis, sphingomyelin abundance diminished in parallel with progressive increase in HDL density from HDL2b (12.8%) to HDL3c (6.2%; P<0.001); in contrast, sphingosine-1-phosphate was preferentially enriched in small HDL3 (40 to 50 mmol/mol HDL) versus large HDL2 (15 to 20 mmol/mol HDL; P<0.01). Small HDL3c was equally enriched in LpA-I particles relative to LpA-I:A-II. The sphingosine-1-phosphate/sphingomyelin ratio correlated positively with the capacities of HDL subspecies to attenuate apoptosis in endothelial cells (r=0.73, P<0.001) and to retard LDL oxidation (r=0.58, P<0.01).


CONCLUSIONS
An elevated sphingosine-1-phosphate/sphingomyelin ratio is an integral feature of small dense HDL3, reflecting enrichment in sphingosine-1-phosphate, a key antiapoptotic molecule, and depletion of sphingomyelin, a structural lipid with negative impact on surface fluidity and LCAT activity. These findings further distinguish the structure and antiatherogenic activities of small, dense HDL.
Kontush
Anatol
A
Université Pierre et Marie Curie-Paris 6, Paris, France. kontush@chups.jussieu.fr
Therond
Patrice
P
Zerrad
Amal
A
Couturier
Martine
M
Négre-Salvayre
Anne
A
de Souza
Juliana A
JA
Chantepie
Sandrine
S
Chapman
M John
MJ
D000975:Antioxidants; D017209:Apoptosis / Q000502:physiology*; D002788:Cholesterol Esters / Q000097:blood* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D050171:Dyslipidemias / Q000097:blood / Q000503:physiopathology; D004789:Enzyme Activation; D006801:Humans; D053440:Lipoproteins, HDL3 / Q000378:metabolism*; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010316:Particle Size; D011336:Probability; D012016:Reference Values; D012680:Sensitivity and Specificity; D013109:Sphingomyelins / Q000096:biosynthesis*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism
D000975:Antioxidants; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D053440:Lipoproteins, HDL3; D008246:Lysophospholipids; D013109:Sphingomyelins; C060506:sphingosine 1-phosphate; D013110:Sphingosine