Lipid exchange of apolipoprotein A-I amyloidogenic variants in reconstituted high-density lipoprotein with artificial...

Area of Science:

• Biochemistry
• Cardiovascular Science
• Biophysics

Background:

• High-density lipoproteins (HDLs) facilitate reverse cholesterol transport, crucial for preventing cardiovascular disease.
• Apolipoprotein A-I (ApoA-I) is the primary protein in HDL, essential for its structure and function.
• Amyloidogenic ApoA-I variants, despite their association with disease, exhibit enhanced cholesterol removal capabilities.

Purpose of the Study:

• To investigate the impact of protein cargo and lipid composition on reconstituted HDL (rHDL) function.
• To explore the structural and functional characteristics of rHDL containing ApoA-I amyloidogenic variants (G26R or L174S).
• To understand how ApoA-I variants influence lipid-protein interactions and cholesterol efflux.

Main Methods:

• Fourier transformed infrared spectroscopy and neutron reflectometry were used to analyze rHDL.
• Small-angle X-ray scattering (SAXS) was employed to determine particle structure.
• Lipid exchange capacities of rHDL particles with artificial membranes were assessed.

Main Results:

• rHDL containing ApoA-I amyloidogenic variants demonstrated a significantly lower capacity for lipid removal compared to native ApoA-I rHDL.
• The lipid removal efficiency was dependent on phospholipid unsaturation and rHDL ultrastructure.
• Distinct structural and functional differences were observed between rHDL particles with native and variant ApoA-I.

Conclusions:

• The protein cargo, specifically ApoA-I variants, plays a critical role in determining rHDL structure and function.
• Amyloidogenic ApoA-I variants may not be ideal for therapeutic rHDL due to reduced lipid removal capacity.
• Understanding lipid-protein interactions is vital for designing effective HDL-based therapies.