Normolipidemic subjects with low HDL cholesterol levels have altered HDL subpopulations

Epidemiological studies have established that plasma concentration of HDL is inversely correlated with the risk of coronary heart disease, even in the absence of increased LDL cholesterol levels. We postulate that specific HDL subpopulations may be responsible for antiatherogenic properties of HDL. HDL subpopulations were quantitated by two-dimensional gel electrophoresis in 79 normolipidemic healthy male subjects. To eliminate the influence of diet, volunteers consumed an average American diet for 6 weeks. After the diet period, subjects were stratified according to their HDL cholesterol (HDL-C) levels to low HDL-C <0.91 mmol/L (<35 mg/dL), medium >0.91 <1.30 mmol/L (>35 <50 mg/dL), and high greater than or equal to 1.30 mmol/L (greater than or equal to 50 mg/dL) groups. Plasma triglycerides and insulin levels were in the normal range, but subjects with low HDL-C levels had higher concentrations of plasma triglycerides and insulin than subjects with medium or high HDL-C concentrations. The absolute concentration (mg/dL) of apoA-I in the largest alpha-migrating HDL subpopulation (alpha(1)) was (P<.01) lower in the low HDL-C subjects compared with the medium and high HDL-C groups. The relative concentration (percent distribution) of apoA-I was decreased (P<.01) in alpha(1) and increased (P<.01) in alpha(3) subpopulations. A positive correlation between HDL-C and alpha(1) (P<.001) and a negative correlation between HDL-C and alpha(3) were observed. The inverse correlation of apoA-I distribution (relative concentration) between alpha(1) and alpha(3) suggests an interconversion of alpha(1) and alpha(3) subpopulations, possibly by cholesteryl ester transfer protein. Pre-beta subpopulations showed an inverse trend with HDL-C, while the pre-alpha subpopulation behaved similarly to the alpha-migrating subpopulation. Colocalization of apoA-I and apaA-II particles in the different HDL subpopulations demonstrated that alpha(1), pre-beta(1), and pre-beta(2) subpopulations are apoA-I-only particles rather than apoA-I:A-II particles.