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Nat Commun. 2016 Nov 21;7:13516. doi: 10.1038/ncomms13516.

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

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
2
Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
3
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
4
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
5
Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
6
Division of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
7
Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
8
W.M. Keck Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
9
Human Genetics &Computational Biomedicine, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.
10
Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
11
Department of Molecular and Clinical Medicine, Sahlgrenska Academy of the University of Gothenburg, Göteborg 41345, Sweden.
12
Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

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.

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