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; William C. Sessa

doi:10.1038/ncomms13516

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

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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 language	English (US)
Article number	13516
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13516
State	Published - 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, Article 13516. https://doi.org/10.1038/ncomms13516

Kraehling, JR, Chidlow, JH, Rajagopal, C, Sugiyama, MG, Fowler, JW, Lee, MY, Zhang, X, Ramírez, CM, Park, EJ, Tao, B, Chen, K, Kuruvilla, L, Larriveé, B, Folta-Stogniew, E, Ola, R, Rotllan, N, Zhou, W, Nagle, MW, Herz, J, Williams, KJ, Eichmann, A, Lee, WL, Fernández-Hernando, C & Sessa, WC 2016, 'Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells', Nature communications, vol. 7, 13516. https://doi.org/10.1038/ncomms13516

@article{b18d78502d9747b08c4ad9f8f3b7595a,

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.",

author = "Kraehling, {Jan R.} and Chidlow, {John H.} and Chitra Rajagopal and Sugiyama, {Michael G.} and Fowler, {Joseph W.} and Lee, {Monica Y.} and Xinbo Zhang and Ram{\'i}rez, {Cristina M.} and Park, {Eon Joo} and Bo Tao and Keyang Chen and Leena Kuruvilla and Bruno Larrive{\'e} and Ewa Folta-Stogniew and Roxana Ola and Noemi Rotllan and Wenping Zhou and Nagle, {Michael W.} and Joachim Herz and Williams, {Kevin Jon} and Anne Eichmann and Lee, {Warren L.} and Carlos Fern{\'a}ndez-Hernando and Sessa, {William C.}",

note = "Funding Information: The initial screen was supported by a pilot grant from the Yale Center for Molecular Discovery and remaining study supported by the NIH (R01 HL64793, R01 HL61371 and P01 HL1070295), and the American Heart Association (Innovative Research Grant and MERIT Grant) to W.C.S. J.R.K. was supported by a fellowship of the German Research Foundation (Deutsche Forschungsgemeinschaft; KR 4268/1-1). The T100 Biacore instrumentation was supported by NIH Award S10RR026992-0110. W.L.L. is supported by grants from NSERC (RGPIN-2015-05802) and the Heart and Stroke Foundation of Canada (G-16-00013521). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = nov,

day = "21",

doi = "10.1038/ncomms13516",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

AU - Kraehling, Jan R.

AU - Chidlow, John H.

AU - Rajagopal, Chitra

AU - Sugiyama, Michael G.

AU - Fowler, Joseph W.

AU - Lee, Monica Y.

AU - Zhang, Xinbo

AU - Ramírez, Cristina M.

AU - Park, Eon Joo

AU - Tao, Bo

AU - Chen, Keyang

AU - Kuruvilla, Leena

AU - Larriveé, Bruno

AU - Folta-Stogniew, Ewa

AU - Ola, Roxana

AU - Rotllan, Noemi

AU - Zhou, Wenping

AU - Nagle, Michael W.

AU - Herz, Joachim

AU - Williams, Kevin Jon

AU - Eichmann, Anne

AU - Lee, Warren L.

AU - Fernández-Hernando, Carlos

AU - Sessa, William C.

N1 - Funding Information: The initial screen was supported by a pilot grant from the Yale Center for Molecular Discovery and remaining study supported by the NIH (R01 HL64793, R01 HL61371 and P01 HL1070295), and the American Heart Association (Innovative Research Grant and MERIT Grant) to W.C.S. J.R.K. was supported by a fellowship of the German Research Foundation (Deutsche Forschungsgemeinschaft; KR 4268/1-1). The T100 Biacore instrumentation was supported by NIH Award S10RR026992-0110. W.L.L. is supported by grants from NSERC (RGPIN-2015-05802) and the Heart and Stroke Foundation of Canada (G-16-00013521). Publisher Copyright: © The Author(s) 2016.

PY - 2016/11/21

Y1 - 2016/11/21

N2 - 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.

AB - 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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VL - 7

JO - Nature communications

JF - Nature communications

M1 - 13516

ER -

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

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