# Macrophage-lipoprotein Interactions

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $422,617

## Abstract

We described a novel mechanism for the hydrolysis of cholesteryl esters in retained and aggregated LDL
(agLDL), which is the predominant form of lipoprotein in atherosclerotic lesions. Macrophages (MΦ) create
tightly sealed compartments that surround the agLDL. They acidify these compartments and secrete
lysosomal enzymes into them, creating a lysosomal synapse. This leads to formation of unesterified
cholesterol outside the cell, which can be delivered to the plasma membrane leading to changes in signal
transduction and foam cell formation. We hypothesize that this mechanism for degrading agLDL has
significant differences compared to phagocytic or endocytic mechanisms and that these differences have
important consequences for the pathophysiology and treatment of atherosclerosis. We will study the cellular
mechanisms that regulate this process (which we call exophagy); better characterize exophagy in vivo; and
explore a novel role for HDL and cyclodextrins in clearing the cholesterol produced by exophagy. (1)
Characterize the mechanisms for extracellular hydrolysis of agLDL. We have used MΦ from knockout mice,
RNAi, and pharmacological agents to identify a role for TLR4, Myd88, SYK, Akt, PI3 kinases, and other
signaling molecules in exophagy. We use three main quantitative assays: lysosome secretion, formation of F-
actin where MΦ contact agLDL, and formation of lipid droplets. We will identify the Rab and SNARE proteins
required for lysosome secretion, and we will identify genes that are activated during exophagy. (2) Determine
the role of lysosomal synapses in atherosclerotic lesions. We will use optical and electron microscopy to
analyze the activity of lysosomal synapses in mouse models of atherosclerosis. We will use bone marrow
transplants into LDL receptor knockout mice to determine the importance of signaling processes. (3)
Characterize HDL interactions with agLDL in contact with MΦ. AgLDL in contact with MΦ has very high levels
of unesterified cholesterol. HDL or cholesterol-balanced cyclodextrins can remove excess cholesterol with no
loss of cholesterol from cells. We will characterize this process and its impact on foam cell formation.

## Key facts

- **NIH application ID:** 9922332
- **Project number:** 5R01HL093324-11
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Frederick R. Maxfield
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,617
- **Award type:** 5
- **Project period:** 2009-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922332

## Citation

> US National Institutes of Health, RePORTER application 9922332, Macrophage-lipoprotein Interactions (5R01HL093324-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9922332. Licensed CC0.

---

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