Journal Article

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

Herz, Joachim, Tao, Bo, Zhang, Xinbo, Rotllan, Noemi, Ola, Roxana, Nagle, Michael W., Rajagopal, Chitra, Eichmann, Anne, Ramírez, Cristina M., Lee, Warren L., Chidlow, John H., Zhou, Wenping, Larriveé, Bruno, Kraehling, Jan R., Lee, Monica Y., Folta-Stogniew, Ewa, Park, Eon Joo, Sessa, William C., Chen, Keyang, Kuruvilla, Leena, Fernández-Hernando, Carlos, Sugiyama, Michael G., Fowler, Joseph W., Williams, Kevin Jon

2016

Overview

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. Atherosclerosis is caused by low-density lipoprotein (LDL) buildup in the vessel wall, a process thought to be mediated by LDL receptor alone. Here, the authors show that the endothelium can uptake LDL via ALK1, a TGFβ signalling receptor, suggesting new therapies for blocking LDL accumulation in the vessel wall.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/80/304 / 631/80/86/2365 / 692/4019/592/75/593/2100 / 82 / 82/103 / 9/10 / Activin Receptors, Type I - genetics / Activin Receptors, Type I - metabolism / Activin Receptors, Type II - genetics / Activin Receptors, Type II - metabolism / Animals / Apolipoproteins B - genetics / Apolipoproteins B - metabolism / Atherosclerosis / Biological Transport / Cardiovascular disease / Cell and Molecular Biology / Cell- och molekylärbiologi / Cells, Cultured / Cholesterol, LDL - genetics / Cholesterol, LDL - metabolism / Cloning, Molecular / Endothelial Cells - metabolism / Endothelium / Gene Knockdown Techniques / Genes / Genome-Wide Association Study / Genomes / Humanities and Social Sciences / Humans / Kinases / Ligands / Low density lipoprotein receptors / Male / Medical Genetics and Genomics / Medicine / Medicinsk genetik och genomik / Mice / multidisciplinary / Physiology / Plasma / R&D / Reproducibility / Research & development / RNA Interference / Science / Science (multidisciplinary) / Standard scores