# Mechanism of ABCA1-mediated CEC to lipidated HDL particles

> **NIH NIH P01** · UNIVERSITY OF CINCINNATI · 2024 · $485,678

## Abstract

SUMMARY (Project 2)
A key theme of this Program Project Grant is that ATP-binding cassette transporter A1 (ABCA1) makes
specific contacts with both lipid-free apolipoprotein A-I (APOA1) and certain high-density lipoprotein (HDL)
subspecies to export lipids from cells to generate mature HDL. This removal of cholesterol from the artery wall
protects against cardiovascular disease. Project 2 picks up on Project 1’s observation that small HDLs are a
subspecies that promotes cholesterol efflux via ABCA1 and that it is especially important for cardioprotection in
diabetes. In addition, we found that the presence of HDL’s second-most abundant protein, apolipoprotein A-II
(APOA2), also promotes ABCA1-mediated cholesterol efflux to fully lipidated HDL particles. These
observations counter the commonly accepted idea that only lipid-poor apolipoproteins can engage ABCA1.
Taking a mechanistic and functional approach, the main goal of Project 2 will be to understand how lipidated
forms of HDL can interact with ABCA1 to promote lipid efflux. The central hypothesis is that the APOA1 in
small HDLs, and in those containing APOA2, undergoes a conformational change, possibly in its C-terminus,
that allows it to interact with ABCA1 (called the “Flipped Ends’ hypothesis). Aim 1 will use high-resolution cryo-
EM and other structural techniques to understand how APOA2 affects APOA1’s structure and its functionality
in cholesterol efflux assays. We will work hand-in-hand with Project 3 to not only model APOA1/A2 interactions
but also to visualize how those particles interact with ABCA1. The specific APOA2 sequences involved will be
identified with an eye toward developing therapeutics that stimulate the transfer of cholesterol from ABCA1 to
lipid-containing HDL particles. Aim 2 will use novel mutations of APOA1 that alter the sizes of HDL particles
along with sophisticated particle reconstitution and structural techniques, such as hydrogen-deuterium
exchange, to identify structural features in small HDL that allow it to engage with ABCA1. We will also identify
and structurally characterize HDL subparticles in human plasma that can interact with ABCA1. Therapeutics
that boost levels of lipid-poor APOA1 as substrates for cholesterol efflux by ABCA1 are being evaluated in
clinical trials. Our work suggests that it may be possible to design therapies that not only increase cholesterol
efflux by ABCA1 to lipid-poor acceptors but also to preformed HDL particles—a pool with much higher capacity
as it comprises the lion’s share of circulating APOA1.

## Key facts

- **NIH application ID:** 10903870
- **Project number:** 5P01HL128203-07
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** W Sean Davidson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,678
- **Award type:** 5
- **Project period:** 2016-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903870

## Citation

> US National Institutes of Health, RePORTER application 10903870, Mechanism of ABCA1-mediated CEC to lipidated HDL particles (5P01HL128203-07). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10903870. Licensed CC0.

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