Abstract
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.
Highlights
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium
Since ANGPT4 is not well characterized as a ligand and GPR182 is an orphan receptor, the initial follow-up focuses on activin-like kinase 1 (ALK1) as an LDL-binding protein mediating LDL uptake and transcytosis
The rationale for identifying new pathways for LDL transit is predicated on the observations that (1) the uptake, transport and retention of sub-endothelial LDL particles can occur in an LDLR independent manner and contribute to the initiation of atherosclerosis[1,2]; (2) hypercholesterolemic levels of LDL will downregulate LDLR by SREBP2-dependent suppression of genes controlling intracellular cholesterol levels[6] and
Summary
In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Additional studies have shown that at least 50% of the LDL that is endocytosed by the endothelium traverses the cells to reach the basolateral side via an unknown active transport mechanism[7,8] and an LDLR independent initial route of LDL permeation into the artery wall has been previously described[9]. The regulated entry of LDL into the vessel wall is essential for both the formation and regression of atheromas With this background in mind, we sought to elucidate the genes required for native LDL uptake into endothelial cells using a genome-wide RNAi approach to target over 18,000 genes followed by high content confocal imaging of fluorescent DiILDL uptake. We characterize one of these hits in detail, ACVRL1 ( called ALK1) which fulfils the criteria for a novel low-affinity, high-capacity receptor for LDL in endothelial cells that functions during hypercholesterolemia and promotes LDL transcytosis
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