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 HDL 3 , 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. In human plasma, five distinct high density lipoprotein (HDL) 1 subpopulations have been identified on the basis of their apparent diameter as determined by using polyacrylamide gradient gel electrophoresis: 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) (1). The heterogeneity of HDL in terms of size distribution may be of physiopathological relevance, and Cheung and coworkers (2) reported significant alterations in HDL size in patients with symptomatic coronary artery disease as compared with healthy control subjects. Interestingly, the presence of coronary artery disease was more strongly associated with abnormalities in HDL particle size distribution than with low HDL cholesterol levels (2). Therefore, these observations raised a considerable interest in identifying the factors that can induce alterations in the relative proportions of plasma HDL 2b , HDL 2a , HDL 3a , HDL 3b , and HDL 3c subfractions in vivo.It is now well established that plasma lipoproteins do ...