High density lipoproteins and reverse cholesterol transport: lessons from mutations.

Abstract

High density lipoproteins (HDL) encompass structurally and functionally heterogeneous particles. Two-dimensional nondenaturing polyacrylamide gradient gel electrophoresis (2D-PAGGE) and subsequent immunoblotting helps to differentiate quantitatively minor HDL-subclasses from the bulk of HDL, which contains apo A-I and has electrophoretic alpha-mobility. Pulse-chase experiments identified the quantitatively minor HDL subclasses prebeta1-LpA-I, gamma-LpE and LpA-IV as initial and fast acceptors of cell-derived cholesterol and alpha-migrating HDL (i.e. alpha-LpA-I) as a late and slow acceptor. In plasmas of patients with certain forms of familial HDL-deficiency such as apo A-I deficiency and Tangier disease, prebeta1-LpA-I, gamma-LpE and LpA-IV represent the only HDL particles and account for the significant residual cholesterol efflux capacity of these plasmas. These particles, however, also fulfill important roles in reverse cholesterol transport of normal plasma. Prebeta1-LpA-I, for example, is generated, during the interconversion of HDL by lipid transfer proteins. Thus, incubation of plasma with phospholipid transfer protein increases the concentration of prebeta1-LpA-I and in parallel increases the cholesterol efflux capacity of plasma indicating that lipid transfer proteins modulate cholesterol efflux by modification of HDL subclass composition. Apo E and gamma-LpE are of special interest for reverse cholesterol transport since macrophages can produce apo E.