Apolipoprotein A1 and high-density lipoprotein limit low-density lipoprotein transcytosis by binding scavenger receptor B1

Abstract

AbstractAtherosclerosis results from the deposition and oxidation of low-density lipoprotein (LDL) and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Numerous studies have now shown that transcytosis transports the circulating LDL across endothelial cells lining the blood vessel. LDL transcytosis is initiated by binding to either Scavenger Receptor B1 (SR-B1) or Activin A receptor-like kinase 1 (ALK1) on the apical side of endothelial cells leading to its transit to the basolateral side. Individuals with elevated levels of circulating high-density lipoprotein (HDL) are partly protected from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (ApoA1), an HDL constituent, can bind to SR-B1, suggesting that ApoA1/HDL may also compete with LDL for SR-B1 binding and thereby oppose its deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescently labelled LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and ApoA1 directly interact and that binding is enhanced when using the cardioprotective variant of ApoA1 termed Milano (ApoA1-Milano). In vivo injection of either wild-type ApoA1 or ApoA1-Milano significantly reduced the acute accumulation of LDL in the atheroprone inner curvature of the murine aorta; inhibition was greater with Milano than the wild-type ApoA1. Together, the results suggest that an additional mechanism for HDL’s atheroprotective effects is attenuating LDL transcytosis through competition for the SR-B1 receptor.