Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

Abstract

Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease.

Endothelial‐protective effects of a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 agonist, SAR247799, in type‐2 diabetes rats and a randomized placebo‐controlled patient trial

“…[5][6][7][8][9][10][11][12] Endothelium and erythrocytes contribute, primarily, to the plasma pool of S1P, and the apoM-component of high-density lipoprotein (HDL) is the major carrier in plasma. 5,13 Not surprisingly, S1P and HDL-bound S1P are reduced in pathologies or conditions associated with endothelial injury, including diabetes, [14][15][16][17][18][19][20][21] metabolic syndrome, 22 myocardial infarction, 20,21 sepsis, 23,24 in-stent restenosis, 25 and in coronary and peripheral artery disease. 26 In patients with cardiovascular disease, higher S1P is associated with cardioprotective settings such as preinfarction angina 27 and coronary collateral circulation.…”

Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins

“…HDL-associated S1P is less susceptible to degradation than free S1P or S1P bound to albumin, suggesting an important role of HDL in regulating the uptake, systemic function and cellular degradation of S1P. Although the mechanism of S1P efflux from cells to HDL is not clearly established, it involves specific transporters, such as adenosine triphosphate (ATP)-binding cassette family transporters [ 56 , 57 , 58 ], including ATP-binding cassette subfamily A member 1 (ABCA1) [ 59 , 60 , 61 ]. S1P plays a central protective role in the pathogenesis of many inflammatory disorders, including asthma, rheumatoid arthritis and atherosclerosis, through modulation of endothelial barrier function [ 62 , 63 , 64 , 65 ] and macrophage function [ 66 ].…”

Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response

“…S1P also has an atheroprotective effect during the progression of atherosclerosis. The antiatherogenic effect of S1P may partially depend on specific action of sphingosine 1 phosphate receptor 1-4 (S1PR1-4) in various types of cells [ 57 ]. It was shown that activation of S1PR1, which is a G-protein receptor, and presence of HDL, which is the main carrier of S1P, can protect macrophages from apoptosis.…”