High density lipoprotein (HDL) particles are characterized by their heterogeneity in composition, structure and biological properties. In addition to the major structural protein apolipoprotein (apo) A1, HDL proteomes and lipidomes show great diversity1, 2. Such constituents presumably carry out the multitude of HDL functions- for example, reverse cholesterol transport, anti-oxidant, anti-inflammatory and anti-infectious properties3.
HDL particles can be further fractionated based on their density, size and electrophoretic mobility4, 5. For instance, sequential ultracentrifugation separates HDL into 2 main subpopulations, namely, lipid-rich large particles named HDL2 and protein-rich small HDL3 populations. These 2 subpopulations present variations in their molecular compositions, which are associated with heterogenous antioxidative, anti-inflammatory and cytoprotective activities4, 5. In addition to the structural and functional heterogeneity, HDL particles are dynamically regulated under various physiological and pathological conditions. For example, oxidation of apo A1 has been associated with inflammatory processes and impairment of protective HDL functions6.
Recently, sphingosine 1-phosphate (S1P), a lipid mediator that acts via G protein-coupled receptors, has featured prominently in HDL biology. The ability of HDL to protect the endothelium7, myocardial ischemic injury and vasodilate8 depends on the S1P cargo. HDL-bound apoM binds, carries and promotes receptor activation in a physiologically-relevant manner9. In addition, HDL-bound S1P appears to be distinct from albumin-bound S1P in the inhibition of endothelial inflammatory processes10, barrier function11 and lymphopoiesis12 suggesting that chaperone-bound S1P acts as a biased agonist to evoke specific biological processes. These observations suggest a major function of S1P in the cardiovascular protection mediated by HDL13. Even though HDL-bound S1P was shown to be decreased in acute coronary syndrome14 and in sepsis15, the relevance of this signaling pathway in chronic diseases that promote cardiovascular risk is not well understood.
Type 1 diabetic patients exhibit increased risk of cardiovascular disease, presumably due to hyperglycemia-induced endothelial injury, oxidative stress, vascular dysfunction and angiopathy of small and large vessels16. In this issue of ATVB, Frej et al. report the role of HDL-bound S1P in type 1 diabetes (T1D)17. In their study, HDL isolated from healthy controls and T1D patients did not show apo M and S1P alterations. However, a shift of apo M and S1P to lipid-rich, light HDL2 particles was seen in T1D. In functional assays, the light HDL2 particles show defective anti-inflammatory functions, which could be due to the reduced ability to signal through the endothelial S1P1 receptor. The authors suggest that increased “dysfunctional HDL” seen in T1D may contribute to the cardiovascular disease risk (Figure 1).
Figure 1.
In normal conditions, HDL3 that chaperones S1P interacts with endothelial cell S1P receptor-1 to protect the endothelium. During type 1 diabetes, lipid-rich/protein-poor HDL2 are more abundant than HDL3 particles. These particles are inefficient to inhibit pro-inflammatory marker expression in endothelial cells. This defect may underlie the increase cardiovascular risk seen in type 1 diabetes.
Interestingly, Frej et al. study further supports the body of work documenting the attenuated HDL-bound S1P level and/or function in chronic diseases. In type 2 diabetes (T2D), glycation of HDL significantly reduces the S1P content of HDL, leading to impairment of cellular protection from oxidative stress. In that study, HDL function recovered by restoring S1P18. In another study focused on patients with metabolic syndrome, reduced HDL-bound S1P resulted in attenuated endothelial nitric oxide synthase (eNOS) activation, which would contribute to vascular dysfunction19. Additionally, HDL dysfunction observed during coronary arterial disease has been linked to a 5-fold decrease in S1P content, likely due to oxidative modifications. Such HDL can be replenished in vitro using S1P donors like red blood cells to regain their protective functions20. Therapeutic administration of reconstituted HDL loaded with S1P reduced ischemia-reperfusion injuries in mouse model of myocardial infarction21.
These recent findings warrant that S1P-centric function of HDL in health and disease needs detailed and comprehensive interrogation in both basic and translational levels. Molecular basis of decreased HDL-S1P, modifications of apo M, and altered S1P-centric signaling properties of HDL2 vs. HDL3 need to be explored. How such alterations lead to pertubations in S1P receptor signaling is not understood at the mechanistic level. However, based on recent developments in HDL biology and therapeutics22, these results further echo the concept that HDL quality rather than quantity is a critical factor to reduce cardiovascular risk.
References
- 1.Kontush A, Lhomme M, Chapman MJ. Unraveling the complexities of the HDL lipidome. J Lipid Res. 2013;54:2950–63. doi: 10.1194/jlr.R036095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Kontush A, Lindahl M, Lhomme M, Calabresi L, Chapman MJ, Davidson WS. Structure of HDL: particle subclasses and molecular components. Handb Exp Pharmacol. 2015;224:3–51. doi: 10.1007/978-3-319-09665-0_1. [DOI] [PubMed] [Google Scholar]
- 3.Navab M, Reddy ST, Van Lenten BJ, Fogelman AM. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol. 2011;8:222–32. doi: 10.1038/nrcardio.2010.222. [DOI] [PubMed] [Google Scholar]
- 4.Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med. 2011;17:594–603. doi: 10.1016/j.molmed.2011.05.013. [DOI] [PubMed] [Google Scholar]
- 5.Kontush A, Chapman MJ. Antiatherogenic small, dense HDL–guardian angel of the arterial wall? Nat Clin Pract Cardiovasc Med. 2006;3:144–53. doi: 10.1038/ncpcardio0500. [DOI] [PubMed] [Google Scholar]
- 6.Huang Y, DiDonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, Kim T, Gerstenecker GS, Gu X, Kadiyala CS, Wang Z, Culley MK, Hazen JE, Didonato AJ, Fu X, Berisha SZ, Peng D, Nguyen TT, Liang S, Chuang CC, Cho L, Plow EF, Fox PL, Gogonea V, Tang WH, Parks JS, Fisher EA, Smith JD, Hazen SL. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med. 2014;20:193–203. doi: 10.1038/nm.3459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, Murakami M, Okajima F. High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arterioscler Thromb Vasc Biol. 2003;23:1283–8. doi: 10.1161/01.ATV.0000079011.67194.5A. [DOI] [PubMed] [Google Scholar]
- 8.Nofer JR, van der Giet M, Tolle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Godecke A, Ishii I, Kleuser B, Schafers M, Fobker M, Zidek W, Assmann G, Chun J, Levkau B. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 2004;113:569–81. doi: 10.1172/JCI18004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Christoffersen C, Obinata H, Kumaraswamy SB, Galvani S, Ahnstrom J, Sevvana M, Egerer-Sieber C, Muller YA, Hla T, Nielsen LB, Dahlback B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc Natl Acad Sci U S A. 2011;108:9613–8. doi: 10.1073/pnas.1103187108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlback B, Kono M, Proia RL, Smith JD, Hla T. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal. 2015;8:ra79. doi: 10.1126/scisignal.aaa2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wilkerson BA, Grass GD, Wing SB, Argraves WS, Argraves KM. Sphingosine 1-phosphate (S1P) carrier-dependent regulation of endothelial barrier: high density lipoprotein (HDL)-S1P prolongs endothelial barrier enhancement as compared with albumin-S1P via effects on levels, trafficking, and signaling of S1P1. J Biol Chem. 2012;287:44645–53. doi: 10.1074/jbc.M112.423426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T. HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature. 2015;523:342–6. doi: 10.1038/nature14462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Levkau B. HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications. Front Pharmacol. 2015;6:243. doi: 10.3389/fphar.2015.00243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gomaraschi M, Ossoli A, Favari E, Adorni MP, Sinagra G, Cattin L, Veglia F, Bernini F, Franceschini G, Calabresi L. Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome. Cardiovasc Res. 2013;100:36–43. doi: 10.1093/cvr/cvt169. [DOI] [PubMed] [Google Scholar]
- 15.Frej C, Linder A, Happonen KE, Taylor FB, Lupu F, Dahlback B. Sphingosine 1-phosphate and its carrier apolipoprotein M in human sepsis and in Escherichia coli sepsis in baboons. J Cell Mol Med. 2016;20:1170–81. doi: 10.1111/jcmm.12831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2014;37:2843–63. doi: 10.2337/dc14-1720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Frej C, Mendez AJ, Ruiz M, Castillo M, Hughes TA, Dahlback B, Goldberg RBA. 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. Arterioscler Thromb Vasc Biol. 2017 doi: 10.1161/ATVBAHA.117.309275. [DOI] [PubMed] [Google Scholar]
- 18.Brinck JW, Thomas A, Lauer E, Jornayvaz FR, Brulhart-Meynet MC, Prost JC, Pataky Z, Lofgren P, Hoffstedt J, Eriksson M, Pramfalk C, Morel S, Kwak BR, van Eck M, James RW, Frias MA. Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection. Arterioscler Thromb Vasc Biol. 2016;36:817–24. doi: 10.1161/ATVBAHA.115.307049. [DOI] [PubMed] [Google Scholar]
- 19.Denimal D, Monier S, Brindisi MC, Petit JM, Bouillet B, Nguyen A, Demizieux L, Simoneau I, Pais de Barros JP, Verges B, Duvillard L. Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment. Arterioscler Thromb Vasc Biol. 2017 doi: 10.1161/ATVBAHA.117.309287. [DOI] [PubMed] [Google Scholar]
- 20.Sattler K, Graler M, Keul P, Weske S, Reimann CM, Jindrova H, Kleinbongard P, Sabbadini R, Brocker-Preuss M, Erbel R, Heusch G, Levkau B. Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content: Correction by Sphingosine-1-Phosphate-Loading. J Am Coll Cardiol. 2015;66:1470–85. doi: 10.1016/j.jacc.2015.07.057. [DOI] [PubMed] [Google Scholar]
- 21.Brulhart-Meynet MC, Braunersreuther V, Brinck J, Montecucco F, Prost JC, Thomas A, Galan K, Pelli G, Pedretti S, Vuilleumier N, Mach F, Lecour S, James RW, Frias MA. Improving reconstituted HDL composition for efficient post-ischemic reduction of ischemia reperfusion injury. PLoS One. 2015;10:e0119664. doi: 10.1371/journal.pone.0119664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet. 2014;384:618–25. doi: 10.1016/S0140-6736(14)61217-4. [DOI] [PubMed] [Google Scholar]