title: Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells.
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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jan R
authors.initials: JR
authors.lastname: Kraehling
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Chidlow
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Chitra
authors.initials: C
authors.lastname: Rajagopal
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Sugiyama
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Fowler
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Monica Y
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Xinbo
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Eon Joo
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Tao
authors.affiliation: Division of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Keyang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Kuruvilla
authors.affiliation: Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Larriveé
authors.affiliation: W.M. Keck Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Folta-Stogniew
authors.affiliation: Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Ola
authors.affiliation: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Wenping
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Human Genetics &Computational Biomedicine, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nagle
authors.affiliation: Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Division of Endocrinology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.|Department of Molecular and Clinical Medicine, Sahlgrenska Academy of the University of Gothenburg, Göteborg 41345, Sweden.
authors.forename: Kevin Jon
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|Departments of Biochemistry and Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
authors.affiliation: Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Vascular Biology and Therapeutics Program (VBT), Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D042783:Endothelial Cells / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D034622:RNA Interference
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse