# Structure-Function Relationship Studies of the Plasma Lipid Transfer Proteins CETP and PLTP

> **NIH NIH R01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2020 · $492,699

## Abstract

Project Summary/Abstract
Cholesteryl ester transfer protein (CETP) mediates the transfer of lipids, including cholesteryl esters
(CEs), triglycerides (TGs) and phospholipids (PLs) between high-density lipoproteins (HDL), low-
density lipoproteins (LDL), and very low-density lipoproteins (VLDL). An elevated level of LDL-
cholesterol (LDL-C) and/or a low level of HDL-cholesterol (HDL-C) in human plasma are major risk
factors for cardiovascular disease (CVD) and familial hyperlipidemia disease. Since increased CETP
can reduce HDL-C concentration and since CETP deficiency is associated with elevated HDL-C
levels, five CETP inhibitors, i.e. Torcetrapib, Anacetrapib, Dalcetrapib, Evacetrapib and Obicetrapib
have been investigated in clinical trials for treating CVD. However, the fact that three inhibitors failed
in large clinical trials reflects our knowledge is little concerning the molecular mechanisms of CETP-
mediated lipid transfer among lipoproteins. In the last funding period, we discovered the CETP
penetrated to HDL and LDL/VLDL, forming a tunnel for CE transfer between lipoproteins. In this
period, we propose to test highlighted residues that play key roles in CE transfer. It can be difficult to
investigate CETP mechanisms using structural methods as interaction with CETP can alter the size,
shape, and composition of lipoproteins, especially HDL. Thus, we propose i) to study the mutated
CETP in CE transfer by all-atom molecular dynamic (MD) simulation and our validated optimized
negative-staining electron microscopy (OpNS-EM) protocol. In OpNS, the flash-fixation of lipoprotein
particles preserves a near native-state conformation for direct visualization of individual molecular or
macromolecular particles. ii) In the last period, we identified a CETP interface that binds to lipoprotein
and patented antibodies as CETP inhibitors for treatment of CVD. In this period, we propose to
validate the antibodies’ function in regulating plasma lipid levels in a rabbit dyslipidemia model. iii) To
further understanding the CETP function in plasma phospholipid transfer, we propose to study the
PLTP interaction with lipoprotein as PLTP has a similar sequence to CETP but a stronger function in
phospholipid transfer among lipoproteins.

## Key facts

- **NIH application ID:** 9836864
- **Project number:** 5R01HL115153-08
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Gang Ren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $492,699
- **Award type:** 5
- **Project period:** 2012-07-23 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836864

## Citation

> US National Institutes of Health, RePORTER application 9836864, Structure-Function Relationship Studies of the Plasma Lipid Transfer Proteins CETP and PLTP (5R01HL115153-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836864. Licensed CC0.

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