# Mechanism of cholesterol regulation by the mitochondrial translocator protein (TSPO)

> **NIH NIH R01** · CORNELL UNIVERSITY · 2021 · $333,607

## Abstract

PROJECT SUMMARY
Free cholesterol is an essential structural component required for integrity and fluidity of membrane bilayers
important for cell signaling and regulation of lipid metabolism. Free cholesterol is also the precursor for the
synthesis of steroid hormones and bile acids. The balance between free cholesterol and its esterified storage
form is tightly regulated by all cells in the body, and is crucial for preventing hypercholesterolemia and
associated disorders. Until recently, it was believed that the translocator protein (TSPO) present in the outer
mitochondrial membrane was a transporter for cholesterol to enter the mitochondria for steroid hormone
production. We overturned this assumption in recent work demonstrating that TSPO is not involved in this
process. This void has refocused attention on elucidating the role of TSPO action. This is of extreme
importance because upregulation of TSPO is seen in multiple human pathologies, and there are currently 24
human clinical trials targeting TSPO for therapeutic or diagnostic purposes. By reexamining the relationship
between TSPO and cholesterol using different Tspo gene deleted models we have identified a novel link
between TSPO and cholesterol esterification. The objective of this application is to elucidate the precise role of
TSPO: (Aim 1) Define the TSPO-mediated mechanism in cholesterol esterification, and (Aim 2) Understand the
in vivo changes to lipid homeostasis in Tspo knockout (Tspo-/-) mice. The experimental plans for this project
extend from molecular characterization of TSPO to studying its functional relevance using in vivo metabolism
models. Using in vitro models, we investigate the importance of cholesterol binding and protein interactions to
TSPO by evaluating specific amino acid mutations to putative binding sites; we also perform metabolomics to
evaluate cellular responses and determine functional integration with known pathways of cholesterol regulation
in cells. Using in vivo models, we examine TSPO effects on lipid metabolism in the liver and white adipose
tissue and the associated impact on plasma lipids. Results from these studies are poised to offer novel insights
into lipid regulation by TSPO that might explain specific pathological dysfunctions observed in atherosclerosis,
non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In addition, knowledge of
TSPO function will be highly relevant to describing the basis of its involvement in pathologies and defining the
principles underlying pharmacological targeting of TSPO for advancing human medicine.

## Key facts

- **NIH application ID:** 10146347
- **Project number:** 5R01DK110059-05
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Vimal Selvaraj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,607
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146347

## Citation

> US National Institutes of Health, RePORTER application 10146347, Mechanism of cholesterol regulation by the mitochondrial translocator protein (TSPO) (5R01DK110059-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146347. Licensed CC0.

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