Multifaceted Physiological Roles of Lipoproteins and Understanding Atherosclerosis: Crosstalk Between Lipoproteins and Bioactive Lipids

Abstract

Traditional management of atherosclerosis focuses primarily on cholesterol and triglycerides; however, lipoproteins also transport bioactive lipids that critically regulate systemic inflammation and metabolic health. This review highlights the diverse physiological and clinical roles of apolipoproteins and bioactive lipids beyond classical lipid accumulation. First, we discuss how hepatic transporters NPC1L1 and ABCG5/8 modulate glucose metabolism and handle non-cholesterol lipids, including phytosterols. Second, we emphasize the apolipoprotein M (ApoM) and sphingosine 1-phosphate (S1P) axis. ApoM protects S1P from degradation and directly mediates the pleiotropic benefits of high-density lipoprotein (HDL), including anti-apoptotic, antithrombotic, and renoprotective effects. Third, reverse translational research utilizing genome-wide association studies identifies apolipoprotein D (ApoD) as a key anti-inflammatory modulator. Finally, clinical lipidomics underscores the importance of “minor” lysophospholipids, such as lysophosphatidylinositol and lysophosphatidylserine, alongside lysophosphatidic acid in the pathogenesis of acute coronary syndrome. Understanding the dynamic crosstalk between lipid transporters, apolipoproteins, and bioactive lipids provides novel mechanistic insights into cardiovascular and metabolic diseases, paving the way for innovative biomarkers and precision therapeutic strategies.