The role of small, dense low density lipoprotein (LDL): a new look

Abstract

Plasma low density lipoprotein (LDL) plays a central role in atherogenesis, and elevated levels of LDL are associated with an increased risk of coronary heart disease (CHD). Studies have now revealed that LDL is structurally heterogeneous, based on its size and density. Patients with combined hyperlipidemia exhibit a lipid profile — the so-called atherogenic lipoprotein phenotype — that is associated with elevated triglyceride levels, low levels of high density lipoprotein and a preponderance of atherogenic, small, dense LDL particles. Such individuals are at an increased risk of CHD events, regardless of their total LDL circulating mass. Evidence suggests that when plasma triglycerides exceed a critical threshold of approximately 133 mg/dl (1.5 mmol/l), this favours the formation of small, dense LDL from larger, less dense species. Lipid-lowering agents that are capable of lowering triglyceride levels below this threshold value will cause a shift to a less dense and, therefore, less atherogenic LDL profile. This effect has been demonstrated for the HMG-CoA reductase inhibitor atorvastatin which, in addition to its ability to markedly decrease the total LDL circulating mass, can also shift the LDL profile towards less dense, larger species. This suggests that atorvastatin may also affect the atherogenic lipoprotein phenotype found in patients with combined hyperlipidemia.

Introduction

Low density lipoprotein (LDL) is the principal cholesterol-carrying lipoprotein in human plasma and, as such, plays a central role in atherogenesis. Elevated levels of LDL are associated with increased risk of coronary heart disease (CHD) [1]. Up until the 1950s, the lipoprotein complexes in the plasma were thought to be homogeneous structures. However, studies by Gofman et al. [2] during the 1950s and 1960s provided the first evidence that LDL may be structurally diverse. Gofman’s group used analytical ultracentrifugation to monitor concentrations of species of differing flotation rates in plasma. LDL was observed to have ‘shoulders’ on a single major peak. Fisher [3] pointed out that the flotation pattern of LDL in hypertriglyceridemics was ‘polydisperse’, with a number of peaks present in the analytical centrifuge profile, whereas normal subjects presented a ‘monodisperse’ pattern.

It was the pioneering work of Krauss and Blanche [4] that established LDL structural heterogeneity to be the norm rather than the exception. Using the high resolution technique of non-denaturing gradient gel electrophoresis, these investigators were able to show that many subjects in the population had an LDL particle size of <250 Å, which was smaller when compared to the more common LDL size of ≈260 Å diameter. Density gradient centrifugation was able to reveal heterogeneity in the LDL density profile. Usually, three maxima are seen in the range 1.019–1.063 g/ml, and these were termed LDL-I, -II and -III [5], [6]. LDL-I has the lowest density (1.025–1.034 g/ml) while LDL-III, also termed small, dense LDL, has the highest density (1.044–1.060 g/ml). Development of techniques in our laboratory to quantify these subfractions has enabled us to study their distribution in the plasma, their relationship to other lipoproteins and their metabolic origins [6], [7].