# Macrophage-Lipoprotein Interactions

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $423,750

## Abstract

Aggregates of lipoproteins that are tightly crosslinked to the extracellular matrix are the major type of
lipoprotein in atherosclerotic lesions. The majority of the cholesterol in these aggregates is unesterified, but it
has been unclear how the cholesteryl esters in the core of retained and aggregated extracellular LDL are
hydrolyzed – especially because a lysosomal hydrolase has been reported to be involved. Our recent studies
demonstrate a novel mechanism for the hydrolysis of cholesteryl esters in the core of retained and aggregated
LDL in which macrophages (M) create tightly sealed compartments that surround portions of the aggregated
LDL. They then acidify these compartments and secrete lysosomal enzymes into them, creating a lysosomal
synapse. It has been shown that the extracellular hydrolysis of cholesteryl esters by lysosomal acid lipase, in a
process called digestive exophagy, leads to production of unesterified cholesterol outside the cell, and
transport of this cholesterol into the cell leads to foam cell formation. The high concentrations of cholesterol in
the aggregated LDL were observed in a preliminary study to lead to the formation of extracellular cholesterol
crystals, which can cause inflammatory responses in M . The overarching hypothesis of this proposal is that
this mechanism for degrading lipoproteins has significant differences as compared to conventional phagocytic
or endocytic mechanisms and that these differences have important consequences in the pathophysiology of
atherosclerosis. Furthermore, understanding this process may lead to improved therapeutic interventions.
 Work in the first aim will characterize the molecular mechanisms of digestive exophagy. This will
include a study of the Rab and SNARE proteins that are required for lysosomal exocytosis. Signaling by Tlr4,
Myd88, PI3-kinase, Akt, Syk, Vav, Cdc42, and other molecules has been shown to be important for digestive
exophagy, and the roles of additional signaling molecules will be explored.
 High concentrations of cholesterol are generated in aggregated LDL, and in Aim 2 formation of
cholesterol crystals and resulting inflammatory activation of M will be examined.
 Work in the third aim will use optical imaging and 3-D electron microscopy (FIB-SEM) to examine the
3D structures of lysosomal synapses in a mouse atherosclerosis model. Formation of lysosomal synapses,
association of cholesterol crystals with retained and aggregated LDL, and inflammatory activation will be
studied in various mouse models of atherosclerosis by optical microscopy.
 Better understanding of the cellular and molecular events occurring in atherosclerotic lesions can lead
to better risk assessments and potentially new therapies.

## Key facts

- **NIH application ID:** 10444272
- **Project number:** 2R01HL093324-12A1
- **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:** 2022
- **Award amount:** $423,750
- **Award type:** 2
- **Project period:** 2009-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444272

## Citation

> US National Institutes of Health, RePORTER application 10444272, Macrophage-Lipoprotein Interactions (2R01HL093324-12A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444272. Licensed CC0.

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