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ResearchIn-Press PreviewMetabolismVascular biology Open Access | 10.1172/JCI190513

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

Ainara G. Cabodevilla,1 Camila Calistru,1 Waqas Younis,1 Dimitris Nasias,1 Tse W.W. Ho,2 Narasimha Anaganti,3 Swati Valmiki,3 Sujith Rajan,3 Jana Gjini,1 Rufina Kore,1 Carmen Hannemann,4 Nicholas O. Davidson,5 Tomas Vaisar,6 Jenny E. Kanter,7 Karin E. Bornfeldt,7 Edward A. Fisher,4 Warren L. Lee,8 Tobias Madl,9 M. Mahmood Hussain,3 and Ira J. Goldberg1

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Kore, R. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Hannemann, C. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

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1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Vaisar, T. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Kanter, J. in: PubMed | Google Scholar |

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Bornfeldt, K. in: PubMed | Google Scholar |

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Fisher, E. in: PubMed | Google Scholar |

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Lee, W. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Madl, T. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Hussain, M. in: PubMed | Google Scholar

1Holman Division of Endocrinology, Diabetes and Metabolism, Department of Me, New York University Grossman School of Medicine, New York, United States of America

2Keenan Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada

3Department of Foundations of Medicine, Diabetes and Obesity Center, New York University Long Island School of Medicine, Mineola, United States of America

4Division of Cardiology and Cardiovascular Research Center, Department of Me, New York University Grossman School of Medicine, New York, United States of America

5Division of Gastroenterology, Washington University School of Medicine, St. Louis, United States of America

6Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Universtiy of Washington, Seattle, United States of America

7Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, United States of America

8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

9Research Unit Integrative Structural Biology, Division Medicinal Chemistry,, Medical University of Graz, Graz, Austria

Find articles by Goldberg, I. in: PubMed | Google Scholar |

Published April 23, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI190513.
Copyright © 2026, Cabodevilla et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 23, 2026 - Version history
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Abstract

Apolipoprotein B (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.

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