Delineating the intricacies of polymorphisms, structures, functions and therapeutic applications of biological high-density lipoprotein-apolipoprotein M: A review.

Apolipoprotein-M (ApoM), primarily associated with high-density lipoproteins (HDL), plays a crucial role in lipid metabolism and cardiovascular health. It facilitates the transport of lipids such as cholesterol and sphingosine-1-phosphate (S1P), contributing to reverse cholesterol transport (RCT), which removes excess cholesterol from peripheral tissues to the liver for excretion. Through its association with HDL and S1P, ApoM exerts anti-inflammatory, anti-thrombotic, and anti-apoptotic effects. The ApoM-S1P complex regulates various cellular, immunological, and physiological processes via S1P receptors, and its dysregulation is linked to metabolic and inflammatory disorders. Reduced plasma ApoM levels are associated with atherosclerosis, diabetes, and chronic systemic inflammation. ApoM levels and paraoxonase-1 activity in early pregnancy correlate with gestational hypertension risk, potentially affecting fetal vascular health. ApoM also functions as a S1P chaperone, and recent research highlights the roles of ApoM/S1P axis and the ApoA1-ApoM (A1M) complex in glucose and lipid metabolism, emphasizing its therapeutic relevance in cardiovascular diseases (CVD), cancer, and diabetes. The ApoM-Fc fusion protein exhibits promising therapeutic potential by reducing fibrosis, enhancing endothelial function, and promoting tissue regeneration. HDL-ApoM macromolecules bind bacterial endotoxins and aids in its clearance. This review explores ApoM gene organization, isoforms, point mutations, protein structure, functions and their relevance for developing novel therapeutics.