# The structural basis for cholesterol esterification in human plasma

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $486,569

## Abstract

Lecithin:cholesterol acyl transferase (LCAT) catalyzes the esterification of a fatty acid to
cholesterol and is responsible for the majority of cholesteryl ester (CE) in the human
circulation. Its activity is dramatically enhanced by cofactor apolipoproteins such as
apolipoprotein (apo)A-I in HDL and apoE in LDL/VLDL and brain lipoproteins. While this
cofactor relationship has been known for decades, our understanding of how apolipoproteins
activate LCAT remains limited. Our preliminary work has shown that LCAT interacts with two
mirror image docking sites within apoA-I that are composed of helix 4 in one apoA-I molecule
and helix 6 of the opposing molecule. When this registry is disrupted, LCAT can still bind HDL
but no longer catalyzes CE formation. We hypothesize that these docking sites orient LCAT
with respect to the lipid faces of HDL particles and may form a conduit by which the particle
core is accessed for deposition of CE. Additionally, we suspect that these sites direct the
cholesterol substrate to the site of LCAT interaction via specific recognition sequences. We
also believe that apoA-II, another highly abundant HDL apolipoprotein, disrupts this
interaction to reduce LCAT activity. Leveraging new experimental tools developed in our
laboratory, we will; 1) define the molecular mechanism for apoA-I activation of LCAT and the
role of these interaction sites, 2) determine how apoA-II attenuates the LCAT reaction and 3)
define the mechanism behind apoE stimulation of LCAT. This work will answer nearly 50 year
old questions about how apolipoproteins enhance LCAT’s ability mediate plasma cholesterol
esterification. In addition, we will translate this knowledge into the design of novel bi-helical
peptides that may form a basis for treating individuals with genetic partial deficiencies of LCAT
activity such as Fish Eye Disease (FED).

## Key facts

- **NIH application ID:** 10450679
- **Project number:** 5R01HL153118-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** W Sean Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,569
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450679

## Citation

> US National Institutes of Health, RePORTER application 10450679, The structural basis for cholesterol esterification in human plasma (5R01HL153118-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450679. Licensed CC0.

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