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 WilliamsAnne Eichmann, Warren L. Lee, Carlos Fernández-Hernando, William C. Sessa

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Article number13516
JournalNature Communications
Volume7
DOIs
StatePublished - Nov 21 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Kraehling, J. R., Chidlow, J. H., Rajagopal, C., Sugiyama, M. G., Fowler, J. W., Lee, M. Y., Zhang, X., Ramírez, C. M., Park, E. J., Tao, B., Chen, K., Kuruvilla, L., Larriveé, B., Folta-Stogniew, E., Ola, R., Rotllan, N., Zhou, W., Nagle, M. W., Herz, J., ... Sessa, W. C. (2016). Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nature Communications, 7, [13516]. https://doi.org/10.1038/ncomms13516