# Chylomicrons and endothelial biology

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $811,326

## Abstract

ABSTRACT
The first steps in atherosclerosis are the transendothelial movement and subendothelial accumulation of
lipoprotein lipid. Endothelial cell (EC) transcytosis of LDL involves two receptors, scavenger receptor-BI (SR-BI)
and activin-like kinase 1 (ALK1). We showed that ECs also internalize undigested chylomicrons via SR-BI and
process them in lysosomes, leading to storage of some lipid as lipid droplets and the release of small extracellular
vesicles (sEVs) that cause lipid accumulation in macrophages. While many have considered chylomicrons as
non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that
lipoprotein entry into the artery is a receptor-mediated process. The overall goal of this project is to determine
how EC chylomicron uptake affects EC biology, delivers lipids to the artery, and accelerates atherosclerosis. In
Aim 1, we propose to determine how triglyceride-rich lipoproteins affect lipid transfer across the vascular
endothelium. We provide preliminary data suggesting that N-terminal apoB18 has separate ligand binding
regions for ALK1 and SR-BI. We will determine whether lipoprotein size or apoB length determines exposure of
these two different regions. We also will determine how sEVs from chylomicron-conditioned ECs cause lipid
accumulation in macrophages and determine the differences between sEVs released from control and
chylomicron-treated ECs. In Aim 2, we propose in vivo studies to determine the role of the EC-chylomicron
uptake pathway in tissue lipid delivery and atherosclerosis. We provide preliminary data suggesting that
chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use
genetically modified mice and knockdown strategies to assess the uptake of LDL and chylomicron lipids into
arteries and will assess whether more extensive atherosclerosis in mice with combined deficiency of LpL and
the LDL receptor is due to hyperchylomicronemia. Finally, we will determine whether AAV-mediated
overexpression of apoB18 reduces EC uptake of apoB lipoproteins in vivo and alters atherosclerosis. Completion
of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, define
a novel pathway for arterial accumulation of atherogenic lipids, and illustrate a possible approach to prevent
these lipids from entering the artery.

## Key facts

- **NIH application ID:** 10757650
- **Project number:** 5R01HL160891-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ira J Goldberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $811,326
- **Award type:** 5
- **Project period:** 2023-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757650

## Citation

> US National Institutes of Health, RePORTER application 10757650, Chylomicrons and endothelial biology (5R01HL160891-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757650. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*