Genetic underpinnings of LDL size and density: a role for hepatic lipase?

Abstract

Plasma lipoprotein abnormalities underlie and may even be essential for the common occurrence of atherosclerotic vascular diseases in Western societies. The abnormalities include elevated concentrations of LDLs and VLDLs and reduced concentrations of HDLs, as generally estimated from measurements of plasma cholesterol, triacylglycerol, and HDL cholesterol. Drug therapies, particularly with compounds of the statin class, have revolutionized the treatment of these diseases and have prevented or postponed them in high-risk individuals. These interventions favorably affect all the major lipoprotein classes, but their effects have been attributed mainly to reduced concentrations of LDL cholesterol. This interpretation is consistent with the reduced incidence of arteriosclerotic manifestations produced by lipidlowering therapies in patients with heterozygous familial hypercholesterolemia, whose predominant lipoprotein abnormality is an elevated concentration of LDL (1). Other studies, however, indicate that the most pronounced lipoprotein abnormalities in patients with early-onset coronary heart disease are high plasma triacylglycerol and low HDL cholesterol, with lesser elevations of LDL cholesterol. But the LDL particles in these individuals are somewhat smaller and more dense than in those with a more favorable lipoprotein profile. As shown by Austin et al (2) at the Donner Laboratory, the occurrence of small, dense LDL particles has some genetic influence, but is more common in men than in premenopausal women and is strongly affected by plasma triacylglycerol concentrations. Persons with plasma triacylglycerol concentrations > 1.69 mmol/L (150 mg/dL) usually have small, dense LDL particles together with low concentrations of HDL cholesterol, whereas persons with triacylglycerol concentrations < 1.24 mmol/L (110 mg/dL) seldom have a predominance of small, dense LDL particles and usually have higher concentrations of HDL cholesterol as well. The constellation of small, dense LDL particles; high plasma triacylglycerol; and low HDL cholesterol has been termed the “atherogenic lipoprotein phenotype” (ALP). The relative contribution of the individual lipoprotein abnormalities that constitute the ALP to the increased risk of atherosclerotic vascular disease is unclear; however, plausible arguments for the atherogenicity of small, dense LDL particles, particularly an increased susceptibility to oxidative modification as compared with larger, more buoyant LDL particles, have heightened interest in this component of the ALP. Predominance of small, dense LDL particles, which is commonly determined by gradient gel electrophoresis of apolipoprotein B‐containing lipoproteins, is called LDL-subclass pattern B, whereas predominance of larger LDL particles is called pattern A. Small, dense LDL particles can be produced by the action of