Introduction: Structure and Metabolism of Plasma Lipoproteins

ABSTRACT

Although it was appreciated at the turn of the century that the lipids of plasma are solubilized by protein,¹ it was another 28 years before the first lipoproteins, high-density lipoproteins (HDL), were isolated.² During the comprehensive efforts to isolate human plasma proteins during World War II, lipoproteins of low density and β electrophoretic mobility were clearly identified and separated from HDL with α mobility.³ Within the next decade, the major antigenic determinants of α and β lipoproteins were shown to be distinct.^4,5 Studies of their hydrodynamic behavior demonstrated the existence of the larger, less dense, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL);⁶ it was established that a strongly antigenic protein was common to these lipoproteins and low density lipoproteins (LDL).⁷ The presence of glutamic acid as the principal N-terminus in LDL^8,9 and one of several in VLDL¹⁰ gave chemical support to the concept that one protein, distinct from the principal proteins in HDL, is virtually the only apolipoprotein in LDL and is present in significant amounts with other apolipoproteins in VLDL. This common protein constituent of LDL and its lipoprotein precursors was termed “apolipoprotein (apo) B” to distinguish it from the protein moiety of HDL (apo A) and the newly recognized proteins of VLDL (apo C).

INTRODUCTION

Current knowledge of the processes of lipid transport in the blood owes much to discoveries of major gene mutations affecting the apolipoproteins, the key enzymes and transfer proteins that control lipid transport, and the cellular receptors that recognize specific apolipoproteins. Indeed, it is difficult to imagine how this field could have reached its present state in the absence of these discoveries, which resulted from clinical investigations of patients manifesting qualitative or quantitative abnormalities of the plasma lipoproteins.

Despite extraordinary advances during the past few years, the basis of much of the variation in lipoprotein concentrations among humans remains poorly understood. However, the primary structure of almost all the proteins that direct the processes of lipid transport in blood plasma is now known, and the discovery of polymorphisms among these proteins and the availability of transgenic mice expressing these proteins and mice in which genes have been deleted by homologous recombination holds much promise for elucidating this variation.

To facilitate understanding of the disorders described in this section, a brief overview of lipoprotein structure, composition, and metabolism is given here (for more extensive discussions, see references¹¹ to¹⁴). The general clinical approach to determining the presenting phenotype is also included (see also references¹⁵ and¹⁶).

GENERAL STRUCTURE AND CLASSIFICATION OF PLASMA LIPOPROTEINS

The lipoproteins normally present in blood plasma vary widely in size, but virtually all but the smallest appear to be microemulsions.¹⁷ Lipoprotein particles are thus spherical and contain a central core of nonpolar lipids (primarily ...