Lipoprotein metabolism and the role of apolipoproteins as metabolic programmers

Abstract

The plasma lipoproteins are large spherical macromolecular structures containing hydrophobic core lipids with phospholipids, cholesterol, and specific proteins (apoproteins) providing an amphipathic interface with the hydrophilic environment of the plasma. The major function of these particles, which are biosynthesized by the intestine and liver, is the transport of dietary or endogenously synthesized lipids to those tissues which utilize exogenous lipids for oxidative metabolism, storage, steroid hormone biosynthesis, or maintenance of their membrane integrity. The triacylglycerol-rich lipoproteins are biosynthesized as metabolically inert particles which are catabolically programmed by postsecretory addition of apoproteins which activate the major lipolytic enzymes, inhibit premature removal, and ensure the later interaction of the degraded particles with specific cellular receptors. During the course of lipolysis, those apoproteins which activate catabolic enzymes are lost from the lipoprotein particles and are transferred to the high-density lipoproteins from which they were initially acquired. High-density lipoprotein also mediates the removal of cholesterol deposited in peripheral tissues as a result of uptake of degraded triacylglycerol-rich lipoproteins. Acquisition of cellular cholesterol by high-density lipoproteins results in its apoprotein-stimulated esterification and the later addition of an apoprotein which mediates receptor recognition and removal of the particle from the plasma. The presence or absence of specific apoproteins on the surface of a lipoprotein particle is modulated by the lipid-binding properties of the apoprotein, the surface lipid composition, and the size of the particle. The nature and mass ratios of these surface lipids are themselves dependent upon the activity of apoprotein-stimulated catabolic enzymes and other proteins which mediate the exchange of surface lipids between lipoprotein particles. Thus the apoproteins are effective programmers of lipoprotein metabolism and fulfil their role as such by cycling, in a directed fashion, between nascent and existing plasma lipoproteins. Genetic defects resulting in a perturbation of this intricate mechanism can lead to premature and pronounced atherosclerosis.