Opposite effects of cholesteryl ester transfer protein and phospholipid transfer protein on the size distribution of plasma high density lipoproteins. Physiological relevance in alcoholic patients

Abstract

The aim of the present study was to investigate the role of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) in determining the size distribution of high density lipoproteins (HDL) in human plasma. Whereas both purified CETP and PLTP preparations were able to promote the size redistribution of isolated HDL3, CETP favored the emergence of small HDL, while PLTP induced the formation of both small and large conversion products. When the total plasma lipoprotein fractions isolated from nine distinct subjects were incubated for 24 h at 37 °C with either purified PLTP or purified CETP, significant alterations in the relative proportions of the five distinct plasma HDL subpopulations, i.e., HDL(2b) (9.71-12.90 nm), HDL(2a) (8.77-9.71 nm), HDL(3a), (8.17-8.77 nm), HDL(3b) (7.76-8.17 nm), and HDL(3c) (7.21-7.76 nm) were also observed. PLTP induced a significant increase in the relative abundance of HDL(2b) (8.66 ± 2.34% versus 7.87 ± 1.83% in controls; p < 0.01) and a significant decrease in the relative abundance of HDL(3a) (32.76 ± 3.42% versus 37.87 ± 2.62% in controls; p < 0.05). In contrast, CETP significantly reduced the relative proportion of HDL(2a) (33.03 ± 2.53% versus 37.56 ± 6.43% in controls; p < 0.01) but significantly increased the relative proportion of both HDL(3b) (21.36 ± 6.97% versus 15.58 ± 7.75% in controls; p < 0.01) and HDL(3c) (3.21 ± 4.84% versus 1.13 ± 0.56% in controls; p < 0.05). Finally, in order to assess further the physiological relevance of in vitro observations, CETP activity, PLTP activity, and HDL size distribution were determined in plasmas from 33 alcoholic patients entering a cessation program. Alcohol withdrawal was associated with (i) a significant increase in plasma CETP activity (173.5 ± 70.5%/h/ml before versus 223.2 ± 69.3%/h/ml after alcohol withdrawal, p = 0.0007), (ii) a significant reduction in plasma PLTP activity (473.9 ± 203.7%/h/ml before versus 312.7 ± 148.4%/h/ml after alcohol withdrawal, p = 0.0001), and (iii) a significant shift of large HDL(2b) and HDL(2a) toward small HDL(3b) and HDL(3c). On the one hand, changes in plasma CETP activity correlated negatively with changes in the proportion of HDL(2a) (r = -0.597, p = 0.0002) and positively with changes in the proportion of HDL(3b) (r = 0.457, p = 0.0075). On the other hand, changes in plasma PLTP activity correlated positively with changes in the proportion of HDL(2b) (r = 0.482, p = 0.0045) and negatively with changes in the proportion of HDL(3a) (r = -0.418, p = 0.0154). Taken together, data of the present study revealed that plasma PLTP and CETP can exert opposite effects on the size distribution of plasma HDL. PLTP can promote the formation of HDL(2b) particles at the expense of HDL(3a), while CETP can promote the formation of HDL(3b) particles at the expense of HDL(2a).