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

Jan R. Kraehling, John H. Chidlow, Chitra Rajagopal, Michael G. Sugiyama, Joseph W. Fowler, Monica Y. Lee, Xinbo Zhang, Cristina M. Ramírez, Eon Joo Park, Bo Tao, Keyang Chen, Leena Kuruvilla, Bruno Larriveé, Ewa Folta-Stogniew, Roxana Ola, Noemi Rotllan, Wenping Zhou, Michael W. Nagle, Joachim Herz, Kevin Jon Williams, Anne Eichmann, Warren L. Lee, Carlos Fernández-Hernando and William C. Sessa ()
Additional contact information
Jan R. Kraehling: Yale University School of Medicine
John H. Chidlow: Yale University School of Medicine
Chitra Rajagopal: Yale University School of Medicine
Michael G. Sugiyama: Keenan Research Centre for Biomedical Science, St. Michael's Hospital
Joseph W. Fowler: Yale University School of Medicine
Monica Y. Lee: Yale University School of Medicine
Xinbo Zhang: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine
Cristina M. Ramírez: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine
Eon Joo Park: Yale University School of Medicine
Bo Tao: Yale University School of Medicine
Keyang Chen: Temple University School of Medicine
Leena Kuruvilla: Yale University School of Medicine
Bruno Larriveé: Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Ewa Folta-Stogniew: W.M. Keck Biotechnology Resource Laboratory, Yale University School of Medicine
Roxana Ola: Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Noemi Rotllan: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine
Wenping Zhou: Yale University School of Medicine
Michael W. Nagle: Human Genetics & Computational Biomedicine, Pfizer Worldwide Research and Development
Joachim Herz: Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center
Kevin Jon Williams: Temple University School of Medicine
Anne Eichmann: Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine
Warren L. Lee: Keenan Research Centre for Biomedical Science, St. Michael's Hospital
Carlos Fernández-Hernando: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine
William C. Sessa: Yale University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13516

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