# SR-BI and PCPE2: Novel partners in bi-directional cholesterol transport

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $690,570

## Abstract

PROJECT SUMMARY
The receptor-ligand complex of scavenger receptor class B type I (SR-BI) and high density lipoprotein (HDL) is
responsible for removal of cholesteryl ester (CE) from the body. This process is crucial to the prevention of
hypercholesterolemia and atherosclerosis. Recently, a study in mice reported that knocking out (KO)
procollagen endopeptidase enhancer 2 (PCPE2), an extracellular matrix protein, resulted in a paradoxical
finding of increased plasma HDL associated with a greater extent of atherosclerosis. Additional investigation
demonstrated that in spite of increased SR-BI levels in livers of PCPE2 KO mice, both plasma cholesterol
clearance and sterol excretion were reduced. Based on these novel findings, we suggest that PCPE2 either
directly interacts with HDL particles or with SR-BI, or a combination of the two, to stabilize HDL interaction(s)
with the receptor and/or provide a scaffold to hold SR-BI in place within the membrane. In this multi-PI
application Dr. Sorci-Thomas and Dr. Sahoo propose to carry out collaborative studies to test the hypothesis
that PCPE2 functionalizes SR-BI receptors on the cell surface to facilitate bidirectional cholesterol
transport. In Aim 1 we investigate how SR-BI works in synergy with PCPE2 to maintain cellular cholesterol
homeostasis. A newly-generated CRISPR/Cas9 PCPE2-deleted 3T3 cell line and a new tissue-specific PCPE2
knockout mouse model will be used to elucidate the physiological relevance of the partnership between SR-BI
and PCPE2, and define how they work together to promote receptor translocation and bidirectional cholesterol
transport. Preliminary data already support a unique physiological role for this partnership in mouse adipose
tissue, in isolated mouse adipocytes and in differentiated 3T3 cells, suggesting that these two proteins play a
significant role in lipid storage. Aim 2 will explore the mechanism defining how SR-BI partners with PCPE2 to
enhance CE uptake from HDL. Specifically, we will determine if PCPE2 facilitates SR-BI oligomerization on the
plasma membrane, a process that is postulated to enable HDL-CE delivery into cells, perhaps by orchestrating
interactions between HDL and SR-BI. This will be tested in both freshly isolated adipocytes as well as in our
PCPE2-deleted 3T3 cell line recently created using CRISPR/Cas9 methods. In Aim 2, utilizing a combination of
mutagenesis, and innovative biochemical and mass spectrometry strategies, we will identify specific regions of
interaction between PCPE2 and SR-BI or PCPE2 and HDL. Together, these innovative studies will exploit the
complementary expertise of the Sorci-Thomas and Sahoo labs to identify novel mechanisms that regulate SR-
BI's function in bidirectional cholesterol transport. The findings from these studies will help identify new
therapeutic strategies for preventing hypercholesterolemia and its associated pathologies such as
atherosclerosis.

## Key facts

- **NIH application ID:** 10153867
- **Project number:** 5R01HL138907-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Daisy Sahoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $690,570
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153867

## Citation

> US National Institutes of Health, RePORTER application 10153867, SR-BI and PCPE2: Novel partners in bi-directional cholesterol transport (5R01HL138907-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10153867. Licensed CC0.

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