Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol

Area of Science:

• Lipidomics
• Cardiovascular Science
• Computational Biology

Background:

• Low high density lipoprotein cholesterol (HDL-C) is a significant risk factor for cardiovascular disease.
• The specific lipid molecular composition of HDL particles in individuals with varying HDL-C levels remains largely uncharacterized.
• Apolipoproteins, particularly apoA-I, are crucial for HDL metabolism, but their interplay with lipid composition is not fully understood.

Purpose of the Study:

• To investigate the lipid molecular composition of HDL particles in subjects with high versus low HDL-C levels.
• To elucidate how lipid composition differences influence HDL particle structure and dynamics.
• To explore the combined utility of lipidomic profiling and molecular dynamics simulations in understanding lipoprotein behavior.

Main Methods:

• Lipidomic analysis of HDL particles isolated from well-characterized cohorts with high and low HDL-C.
• In silico reconstitution of HDL particles using experimental lipid composition data.
• Large-scale molecular dynamics simulations to analyze HDL particle structure and lipid distribution.

Main Results:

• Subjects with low HDL-C exhibited elevated triacylglycerols and reduced lysophosphatidylcholines and sphingomyelins in their HDL particles.
• Molecular dynamics simulations confirmed alterations in HDL particle size and revealed distinct spatial arrangements of lipids.
• Specifically, low HDL-C particles showed a higher surface concentration of triacylglycerols.

Conclusions:

• The study provides the first comprehensive molecular lipid profile of HDL particles associated with low HDL-C levels.
• Altered lipid composition significantly impacts HDL particle structure, including lipid distribution, which may affect HDL function.
• Combining lipidomics with dynamic modeling offers a powerful approach to dissecting lipoprotein structure-function relationships and their role in cardiovascular disease.