High density lipoproteins and reverse cholesterol transport: lessons from mutations

Area of Science:

• Lipid metabolism and cardiovascular research.
• Biochemistry of lipoprotein particles.
• Analysis of high-density lipoprotein (HDL) heterogeneity.

Background:

• High-density lipoproteins (HDL) are heterogeneous, with distinct subclasses playing varied roles.
• Understanding HDL subclass function is key to reverse cholesterol transport.
• Familial HDL deficiencies highlight the importance of specific HDL particles.

Purpose of the Study:

• To quantitatively differentiate and characterize minor HDL subclasses.
• To investigate the role of specific HDL subclasses in cholesterol efflux.
• To explore the impact of lipid transfer proteins on HDL composition and function.

Main Methods:

• Two-dimensional nondenaturing polyacrylamide gradient gel electrophoresis (2D-PAGGE) combined with immunoblotting.
• Pulse-chase experiments to track HDL particle dynamics.
• Incubation of plasma with phospholipid transfer protein to assess functional changes.

Main Results:

• Identified prebeta1-LpA-I, gamma-LpE, and LpA-IV as initial, fast cholesterol acceptors.
• Demonstrated that these minor subclasses are the sole HDL in certain deficiencies, retaining cholesterol efflux capacity.
• Showed that phospholipid transfer protein increases prebeta1-LpA-I and cholesterol efflux, indicating modulation of HDL subclass composition.

Conclusions:

• Minor HDL subclasses are essential for cholesterol efflux, even in HDL-deficient states.
• Lipid transfer proteins actively modify HDL composition, influencing plasma cholesterol efflux capacity.
• Apolipoprotein E-containing HDL subclasses are significant for reverse cholesterol transport due to macrophage production of apo E.