# Atheroprotection  via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2022 · $403,750

## Abstract

Although high plasma concentrations of LDL-C (“bad cholesterol”) are associated with atherosclerotic
cardiovascular disease (ACVD), statins reduce plasma LDL-C and with it ACVD. In contrast, high density
lipoprotein-cholesterol (HDL-C; “good cholesterol”) varies inversely with ACVD. However attempts to reduce
ACVD via increased plasma HDL-C levels have failed. New evidence suggests that HDL quality is more
important than quantity and that its ability to remove free cholesterol (FC) from macrophages (MΦ), an important
cell type in ACVD, is its most important atheroprotective quality. This process, MΦ-FC efflux, initiates the FC
transfer to the intestine for disposal—an atheroprotective process. Paradoxically, patients with very high plasma
HDL-C levels are at high ACVD risk; the underlying mechanism is unknown, and currently there are no
interventions that reverse high HDL-C levels in a cardioprotective way. We hypothesize that the underlying
cause of ACVD in patients with very high plasma HDL-C levels is too much HDL that contains high amounts of
FC, which transfers freely among cells and lipoproteins. This state makes FC highly bioavailable so that rather
than removing FC from the arterial wall, FC-rich HDL transfers FC to arterial-wall MΦ—an atherogenic process.
Using a mouse model of ACVD with underlying high HDL-C levels (SR-B1-/- mouse) we plan to identify HDL-FC
bioavailability as a driver of ACVD and show that treatment with an HDL-lowering bacterial protein (serum opacity
factor), delivered with an adeno-associated virus prevents/reverses ACVD. Within this ACVD-HDL axis, we
propose the following specific aims:
Aim 1—To compare the plasma clearance kinetics of wild-type and SR-B1-/- HDL-[3H]FC and cholesteryl ester
(CE) in wild-type and SR-B1-/- mice, simultaneously identifying the tissue sites of [3H]FC and [3H]CE accretion,
and the effects of AAVSOF vs. AAVGFP on these kinetics and tissue distributions.
Aim 2a—To test the hypothesis that FC flux between HDL and J774 MΦ switches from efflux to influx with
increasing HDL-FC bioavailability, which is a function of HDL particle concentration and HDL-FC content (mol%
FC). Aim 2b—Concurrently with Aim 1, to test the hypothesis that HMGCoA reductase and ACAT activities
decrease and increase, respectively, MΦ-FC content as effected by increasing HDL-FC bioavailability. Aim 2c—
To test the hypothesis that increased HDL-FC bioavailability induces foam cell formation in J774 MΦ.
Aim 3—To test the hypothesis that reduction of HDL-FC by AAVSOF vs. AAVGFP delivery prevents and/or reverses
atherosclerosis in SR-B1-/- mice.
Completion of these aims will provide a compelling rationale ●for studies to determine whether high plasma HDL-
FC is associated with ACVD in patients with high HDL-C and ●for the development of drugs that lower HDL-FC.

## Key facts

- **NIH application ID:** 10308045
- **Project number:** 5R01HL149804-03
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Henry J. Pownall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2019-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308045

## Citation

> US National Institutes of Health, RePORTER application 10308045, Atheroprotection  via Reduced Plasma High Density Lipoprotein-Free Cholesterol Bioavailability (5R01HL149804-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308045. Licensed CC0.

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