# Cellular cholesterol movement in cardiovascular disease

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $670,800

## Abstract

Project 3: Sterol Transport Pathways in Cardiovascular Disease
ABSTRACT
The objective of Project 3 is to define fundamental mechanisms that regulate cellular lipid flux and to elucidate
their impact on systemic metabolism. Dissecting signaling pathways that govern how cells store, transport, and
metabolize lipids is expected to uncover new opportunities for therapeutic intervention in metabolic disease.
Although nonvesicular cholesterol transport has long been hypothesized to be critical for lipid homeostasis in
mammalian cells, the underlying mechanisms have remained obscure. We have discovered a novel transporter
called Aster-B that appears to fill this important gap in our understanding of sterol transport. Aster-B is a
previously uncharacterized protein that facilitates the direct transport of cholesterol from the plasma membrane
(PM) to the ER. We propose a series of molecular, cell biological, and mouse studies to investigate the roles of
the Aster-B cholesterol transport pathway in physiology and disease. Aim 1 is to elucidate the role of Aster-B in
cellular cholesterol transport, efflux, and esterification. We identified Asterb as a novel cholesterol-responsive
LXR target gene. Gain or loss of Aster-B alters cholesterol distribution and impairs cholesterol ester synthesis in
response to cholesterol loading. Using biochemical approaches and complementary imaging modalities
including electron and live-cell microscopy, we will define the mechanism of action of Aster-B and its role in
macrophage sterol flux. Aim 2 is to determine the impact of Aster-B on sterol transport in vivo. Preliminary data
indicate that Asterb is most highly expressed in macrophages, adrenal gland, and gonads. We will determine
the effect of loss of Aster-B expression on whole-body and tissue-specific lipid homeostasis. We hypothesize
that Aster-B is a critical mediator of cellular cholesterol transport downstream of the HDL receptor SR-BI. Aim 3
is to define the contribution of the macrophage Aster pathway to atherosclerosis. The LXR pathway is one of the
strongest known determinants of atherosclerotic lesion development. Our observation that Aster-B expression
is regulated by LXRs suggests that Aster-dependent cholesterol transport may impact macrophage foam cell
formation and the development of atherosclerosis. We will test the impact of gain or loss of Aster function on
macrophage cholesterol uptake and efflux. We will perform bone marrow transplant studies into LDLR-deficient
mice to test the impact of Aster-B deficiency on lesion formation. Aim 4 is to identify additional components of
the Aster pathway. We will perform protein-interaction screens using a biotin proximity labeling strategy. We will
perform a chemoproteomic screen using HDL particles loaded with a cholesterol-mimetic probe that can be
crosslinked to proteins and retrieved using a click-chemistry handle. This application leverages the unique and
complementary strengths of each member of our PPG, br...

## Key facts

- **NIH application ID:** 10613974
- **Project number:** 5P01HL146358-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** PETER J TONTONOZ
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $670,800
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10613974

## Citation

> US National Institutes of Health, RePORTER application 10613974, Cellular cholesterol movement in cardiovascular disease (5P01HL146358-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10613974. Licensed CC0.

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