Cholesterol Efflux Efficiency of Reconstituted HDL Is Affected by Nanoparticle Lipid Composition
Shifa Jebari-Benslaiman1,2, Kepa B Uribe3, Asier Benito-Vicente1,2
1Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC)), 48940 Leioa, Spain.
Insights
The study found that dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) nanoparticles are most effective at removing excess cholesterol, a key factor in cardiovascular disease (CVD). These findings highlight the importance of nanoparticle composition for developing better CVD therapies.
Area of Science:
- Biochemistry
- Nanotechnology
- Cardiovascular Medicine
Background:
- Cardiovascular disease (CVD) is a leading global cause of death, primarily driven by atherosclerosis.
- Atherosclerosis involves the buildup of low-density lipoproteins in artery walls.
- Reconstituted high-density lipoproteins (rHDLs) are being developed as therapies to remove excess cholesterol.
Purpose of the Study:
- To evaluate the cholesterol efflux efficiency of rHDLs with varying lipid compositions.
- To understand how lipid composition influences the effectiveness of cholesterol removal by rHDLs.
- To mimic different in vivo high-density lipoprotein (HDL) maturation stages using rHDLs.
Main Methods:
- Investigated cholesterol efflux activity of various rHDL formulations, including soybean PC (Soy-PC), DPPC, and combinations with cholesterol (Chol) and lysophosphatidylcholine (LysoPC).
- Utilized multiple cell models to assess the impact of rHDL lipid composition on cholesterol removal.
- Examined the role of the ABCA1 transporter in potentiating cholesterol efflux.
Main Results:
- DPPC-based rHDLs demonstrated the highest efficiency in cholesterol efflux across all tested cellular models.
- Cholesterol removal by DPPC rHDLs was enhanced when the ABCA1 transporter was upregulated.
- The lipid composition significantly contributes to the effectiveness of cholesterol removal by rHDLs.
Conclusions:
- DPPC rHDLs, resembling nascent HDL, are superior in inducing cholesterol efflux.
- Enhanced efflux is attributed to cholesterol's binding affinity to saturated phospholipids and favorable bilayer curvature.
- Physicochemical properties of rHDLs are critical for designing effective cholesterol-removing nanoparticles for CVD therapy.
Abstract:
Cardiovascular disease (CVD), the leading cause of mortality worldwide is primarily caused by atherosclerosis, which is promoted by the accumulation of low-density lipoproteins into the intima of large arteries. Multiple nanoparticles mimicking natural HDL (rHDL) have been designed to remove cholesterol excess in CVD therapy. The goal of this investigation was to assess the cholesterol efflux efficiency of rHDLs with different lipid compositions, mimicking different maturation stages of high-density lipoproteins (HDLs) occurring in vivo.
Methods:
the cholesterol efflux activity of soybean PC (Soy-PC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), DPPC:Chol:1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC) and DPPC:18:2 cholesteryl ester (CE):LysoPC rHDLs was determined in several cell models to investigate the contribution of lipid composition to the effectiveness of cholesterol removal.
Results:
DPPC rHDLs are the most efficient particles, inducing cholesterol efflux in all cellular models and in all conditions the effect was potentiated when the ABCA1 transporter was upregulated.
Conclusions:
DPPC rHDLs, which resemble nascent HDL, are the most effective particles in inducing cholesterol efflux due to the higher physical binding affinity of cholesterol to the saturated long-chain-length phospholipids and the favored cholesterol transfer from a highly positively curved bilayer, to an accepting planar bilayer such as DPPC rHDLs. The physicochemical characteristics of rHDLs should be taken into consideration to design more efficient nanoparticles to promote cholesterol efflux.
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