# Effects of A1AT on PCSK9 expression and function

> **NIH NIH SC1** · NORTH CAROLINA CENTRAL UNIVERSITY · 2020 · $370,000

## Abstract

PROJECT SUMMARY
 Heart disease is the principal cause of death and disability for both men and women in the US accounting
for 40% of all annual deaths. A high cholesterol level, especially of low density lipoprotein (LDL), is a well-known
risk factor for this disease. The key atherogenic property of LDL particles involves the formation of
atherosclerotic plaques. Since the hepatic LDL receptor is the major determinant of plasma LDL-cholesterol
levels, a greater understanding of the regulatory mechanisms that control the expression of the LDL receptor is
essential. Proprotein convertase subtilisin/kexin-9 (PCSK9) is a well-known indirect regulator of plasma LDL
levels by controlling the number of LDL receptor molecules expressed at the plasma membrane. Preliminary
studies in our laboratory suggest that alpha-1-antitrypsin (A1AT) directly interacts with PCSK9 in the medium of
cells and prevents the formation of PCSK9/LDL receptor complexes in vitro. A1AT also promotes the removal
of PCSK9 from the medium of the cells, but the mechanism for this removal is currently unknown. The long-term
objective of this research project is to characterize the molecular mechanisms involved in the A1AT-dependent
regulation of PCSK9 expression and function. The major impact of this project will be the identification of an
endogenous inhibitor of PCSK9 could lead to the development of diagnostic tests to identify patients and provide
them with the best and safest treatment options. Also, this inhibitor could become an alternative treatment for
patients that develop intolerance to currently available anticholesterolemic drugs. Based on this, we
hypothesized that the levels of LDL receptor protein that is available to bind and remove LDL from the circulation
are conditioned to the ratio between A1AT and PCSK9. In this research proposal, we will test this hypothesis
through the following specific aims: Aim I: To find common regulators of A1AT and PCSK9 expression; Aim
II: To detect critical protein regions in A1AT that influences PCSK9 expression/function; Aim III: To identify the
pathway(s) involved in the internalization of PCSK9/A1AT complexes.

## Key facts

- **NIH application ID:** 9993543
- **Project number:** 5SC1GM131974-02
- **Recipient organization:** NORTH CAROLINA CENTRAL UNIVERSITY
- **Principal Investigator:** Dayami Lopez
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,000
- **Award type:** 5
- **Project period:** 2019-08-09 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993543

## Citation

> US National Institutes of Health, RePORTER application 9993543, Effects of A1AT on PCSK9 expression and function (5SC1GM131974-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9993543. Licensed CC0.

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