# Mechanisms of nonvesicular cholesterol transport

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $727,059

## Abstract

ABSTRACT
Our long-term objective is to define cellular pathways that regulate cellular cholesterol flux and to elucidate
their impact on metabolism and pathology. Most of the free cholesterol in mammalian cells resides in the
plasma membrane (PM). We previously showed that the Aster family of nonvesicular lipid transporters are
critical for the movement of cholesterol from the PM to the ER in most if not all mammalian cells. Asters are
ER-anchored proteins that bind cholesterol and facilitate the formation of ER-PM contacts in response to
elevated accessible PM cholesterol levels. Although they are required for efficient PM to ER transport, Asters
almost certainly do not act alone. Other factors are very likely to be involved in the spatial organization of
accessible PM cholesterol, the formation and stabilization of PM-ER contacts, the movement of Aster proteins
from ER to PM, and the channeling of PM cholesterol to specific regions of the ER for SREBP regulation or
esterification by ACAT. The identity of such factors is currently unknown. A complete understanding of how
cellular cholesterol is transported in vascular cells through nonvesicular pathways will fill important knowledge
gaps and may uncover new opportunities for therapeutic intervention in cholesterol movement in the setting of
cardiovascular disease. Specific Aim 1 will identify new players in nonvesicular lipid transport. We have
devised proximity labeling strategies to identify proteins that localize with Asters to ER-PM contacts in a
cholesterol-dependent manner. Specific Aim 2 will define the physiological functions of Aster interactors in
cellular and systemic lipid transport. We will validate the functional importance of Snap23 and other factors for
lipid metabolism and inflammation in cell culture and animal models. Specific Aim 3 will elucidate the
mechanisms and physiological consequences of Aster phosphorylation. We have discovered that Aster-A is
phosphorylated in response to cholesterol loading or LPS stimulation. Dissecting the molecular mechanisms
that control PM cholesterol levels in cells, and thereby impact lipid metabolism and inflammation, is central to
understanding cell physiology and is expected to provide insight into the etiology and future therapy of
metabolic disease.

## Key facts

- **NIH application ID:** 10991543
- **Project number:** 1R01HL175773-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** PETER J TONTONOZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $727,059
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991543

## Citation

> US National Institutes of Health, RePORTER application 10991543, Mechanisms of nonvesicular cholesterol transport (1R01HL175773-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10991543. Licensed CC0.

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