# Blood TG clearance and vascular biology

> **NIH NIH P01** · NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE · 2024 · $647,320

## 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non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that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 Project 3 (P3) 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 (TRLs) from the liver and intestines are
internalized and either processed within ECs or transcytosed. To do this, we will use mice with selective knockout
of liver and intestinal microsomal triglyceride transfer protein (MTP) obtained from Dr. Hussain (P1) to determine
lipoprotein characteristics that determine their interaction with SR-BI and ALK1. We will also determine how
lipoproteins created with liver FIT2 knockout (P2) affect EC inflammation and the production and composition of
EC released sEVs. Our preliminary data show that the N-terminal region of apoB has separate ligand binding
regions for ALK1 and SR-BI and this aim will determine why and how lipoprotein uptake via each of these
receptors affects ECs. In Aim 2, we propose in vivo studies to determine whether postprandial lipemia leads to
EC inflammation and whether the site of origin of these TRLs determines their effects on arterial ECs. We provide
preliminary data suggesting that chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase
atherosclerosis. We will use N-terminal fragments of apoB to reduce lipoprotein uptake into ECs to determine
role(s) of ALK1 and SR-BI in EC inflammation and atherosclerosis. Completion of the proposed studies promises
to alter our view of the relationship of chylomicrons to vascular disease, determine whether TRLs from liver and
intestine have similar effects on ECs, and define a novel approach to atherosclerosis prevention.

## Key facts

- **NIH application ID:** 10834210
- **Project number:** 5P01HL160470-02
- **Recipient organization:** NEW YORK UNIVERSITY D/B/A NYU LONG ISLAND SCHOOL OF MEDICINE
- **Principal Investigator:** Ira J Goldberg
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,320
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834210

## Citation

> US National Institutes of Health, RePORTER application 10834210, Blood TG clearance and vascular biology (5P01HL160470-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834210. Licensed CC0.

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