# ABCA1/G1 and LXRs in Atherogenesis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $502,605

## Abstract

Despite the success of LDL lowering therapies there is a need for new treatments to reduce the
large burden of residual atherosclerotic cardiovascular disease. Increasing beneficial HDL
functions is one potential approach. HDL infusion therapies and small molecule LXR activators,
induce cholesterol efflux from macrophage foam cells and reduce atherosclerosis in animal
models. However, the underlying protective mechanisms are incompletely understood and this
has delayed clinical development. Cholesterol efflux pathways appear to exert anti-atherogenic
effects by suppressing inflammatory responses in myeloid cells. The efflux of cholesterol to
ApoA-1 and HDL is facilitated by the ATP binding cassette transporters ABCA1 and ABCG1,
which are induced by LXRs. Our recent studies in mice with myeloid cell deficiency of these
transporters have revealed a major role of cholesterol efflux pathways in suppressing the
inflammasome. These mice showed inflammasome activation in macrophages and neutrophils.
Unexpectedly, they also displayed prominent neutrophil extracellular traps (NETs) in lesions.
Deficiency of inflammasome components reduced lesion area and abolished NETs, showing for
the first time that inflammasome activation promotes lesional NETosis. The recent CANTOS trial
has highlighted the importance of inflammasome activation and IL-1b production in human
coronary heart disease. Other studies have shown a role of NETosis in atherogenesis and plaque
instability. Thus, our studies showing that HDL and cholesterol efflux pathways can suppress
these processes have major translational potential, especially in conditions where ABCA1/G1 are
suppressed and HDL levels are low, such as Type 2 diabetes. The goal of this proposal is to
evaluate mechanisms linking cholesterol efflux pathways to atherogenic inflammation. Aim 1 will
explore mechanisms linking ABCA1/G1-mediated cholesterol efflux to inflammasome activation,
atherogenesis and NETosis. Aim 2 will explore the mechanisms and significance of rHDL-
mediated cholesterol efflux in macrophage inflammation. Aim 3 will assess new mechanisms
connecting LXR activation to suppression of atherogenic inflammation. These studies may
provide novel mechanistic insights stimulating the development of new treatments for
atherosclerosis.

## Key facts

- **NIH application ID:** 10406915
- **Project number:** 5R01HL107653-12
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ALAN richard TALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,605
- **Award type:** 5
- **Project period:** 2011-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406915

## Citation

> US National Institutes of Health, RePORTER application 10406915, ABCA1/G1 and LXRs in Atherogenesis (5R01HL107653-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406915. Licensed CC0.

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