The N-terminus of apolipoprotein B mediates the interaction of atherogenic lipoproteins with endothelial cells
Ainara G. Cabodevilla, Camila Calistru, Waqas Younis, Dimitris Nasias, Tse W.W. Ho, Narasimha Anaganti, Swati Valmiki, Sujith Rajan, Jana Gjini, Rufina Kore, Carmen Hannemann, Nicholas O. Davidson, Tomas Vaisar, Jenny E. Kanter, Karin E. Bornfeldt, Edward A. Fisher, Warren L. Lee, Tobias Madl, M. Mahmood Hussain, Ira J. Goldberg
Ainara G. Cabodevilla, Camila Calistru, Waqas Younis, Dimitris Nasias, Tse W.W. Ho, Narasimha Anaganti, Swati Valmiki, Sujith Rajan, Jana Gjini, Rufina Kore, Carmen Hannemann, Nicholas O. Davidson, Tomas Vaisar, Jenny E. Kanter, Karin E. Bornfeldt, Edward A. Fisher, Warren L. Lee, Tobias Madl, M. Mahmood Hussain, Ira J. Goldberg
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Research Article Metabolism Vascular biology

The N-terminus of apolipoprotein B mediates the interaction of atherogenic lipoproteins with endothelial cells

Abstract

Apolipoprotein B–containing (APOB-containing) lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs. APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1-mediated uptake of APOB100-containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.

Authors

Ainara G. Cabodevilla, Camila Calistru, Waqas Younis, Dimitris Nasias, Tse W.W. Ho, Narasimha Anaganti, Swati Valmiki, Sujith Rajan, Jana Gjini, Rufina Kore, Carmen Hannemann, Nicholas O. Davidson, Tomas Vaisar, Jenny E. Kanter, Karin E. Bornfeldt, Edward A. Fisher, Warren L. Lee, Tobias Madl, M. Mahmood Hussain, Ira J. Goldberg

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Figure 4

Treatment with APOB18-AAV inhibits aortic EC chylomicron uptake in vivo.

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Treatment with APOB18-AAV inhibits aortic EC chylomicron uptake in vivo....
(A) Lplfl/fl and iLpl–/– mice were injected intravenously with 2.00 × 1011 vg control (null) or APOB18 liver-targeted AAV8. (B) APOB18 was detected by immunoblot in the plasma of APOB18-AAV–treated mice 2 weeks after injection. (C) iLpl–/– mice treated with APOB18-AAV exhibit significantly fewer postprandial lipid droplets (green) in their aortic endothelium 180 minutes after a gavage with 200 μL olive oil. Scale bars: 10 μm. (D) Null and APOB18-AAV–treated Lplfl/fl mice were given DiI-labeled chylomicrons (red) by intravenous injection and euthanized 15 minutes later. Scale bars: 10 μm. Mice treated with APOB18-AAV exhibited significantly fewer chylomicrons in their aortic endothelium. *P < 0.01, **P < 0.001, unpaired 2-tailed Student’s t test.