Phospholipid transfer protein (PLTP) remodels high density lipoproteins (HDL) into large and small particles. It also mediates the dissociation of lipid-poor or lipid-free apolipoprotein A-I (apoA-I) from HDL. Remodeling is enhanced markedly in triglyceride (TG)-enriched HDL (Rye, K.-A., Jauhiainen, M., Barter, P. J., and Ehnholm. C. (1998) J. Lipid. Res. 39, 613-622). This study defines the mechanism of the remodeling of HDL by PLTP and determines why it is enhanced in TG-enriched HDL. Homogeneous populations of spherical reconstituted HDL (rHDL) containing apoA-I and either cholesteryl esters only (CE-rHDL; diameter 9.3 nm) or CE and TG in their core (TG-rHDL; diameter 9.5 nm) were used. After 24 h of incubation with PLTP, all of the TG-rHDL, but only a proportion of the CE-rHDL, were converted into large (11.3-nm diameter) and small (7.7-nm diameter) particles. Only small particles were formed during the first 6 h of incubation of CE-rHDL with PLTP. The large particles and dissociated apoA-I were apparent after 12 h. In the case of TG-rHDL, small particles appeared after 1 h of incubation, while dissociated apoA-I and large particles were apparent at 3 h. The composition of the large particles indicated that they were derived from a fusion product. Spectroscopic studies indicated that the apoA-I in TG-rHDL was less stable than the apoA-I in CE-rHDL. In conclusion, these results show that (i) PLTP mediates rHDL fusion, (ii) the fusion product rearranges by two independent processes into small and large particles, and (iii) the more rapid remodeling of TG-rHDL by PLTP may be due to the destabilization of apoA-I. Phospholipid transfer protein (PLTP)1 transfers phospholipids (PL) between high density lipoproteins (HDL) and very low density lipoproteins as well as between different particles within the HDL fraction (1, 2). It also remodels HDL into large and small particles in a process that is accompanied by the dissociation of lipid-poor or lipid-free apolipoprotein A-I (apoA-I) (3-8). Remodeling is enhanced markedly in HDL that contain triglyceride (TG) in their core (9). Evidence of the importance of PLTP in HDL metabolism comes from studies of mice transgenic for human PLTP. These animals have increased levels of pre-␤ 1 -migrating HDL, the initial acceptors of cellular cholesterol in the first step of the reverse cholesterol pathway, and are also resistant to intracellular cholesterol accumulation (10 -12). Studies of PLTP knockout mice have shown that PLTP is essential for maintaining normal HDL levels in plasma (13). Moreover, it has been reported recently that PLTP-mediated transfers of phospholipids between HDL and other lipoprotein classes are not interchangeable with the phospholipid transfers that are mediated by cholesteryl ester transfer protein (CETP) (14).The mechanism of the remodeling of HDL by PLTP is poorly understood. Although there is evidence that particle fusion and the dissociation of lipid-poor or lipid-free apoA-I are involved (7,8), nothing is known about how the interaction of PLTP wi...

Objective-The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial. Methods and Results-We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr Ϫ/Ϫ background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe Ϫ/Ϫ background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr Ϫ/Ϫ background displayed no change in atherosclerotic lesion area. Conclusions-These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis. Key Words: lipid and lipoprotein metabolism Ⅲ genetically altered mice Ⅲ pathophysiology of atherosclerosis T he ATP binding cassette transporter, subfamily A, member 1 (ABCA1) regulates the rate-limiting step in the biogenesis of high-density lipoprotein (HDL) particles by mediating the efflux of cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) and therefore plays a critical role in reverse cholesterol transport. 1 Mutations in ABCA1 in humans cause Tangier disease (TD), characterized by nearly absent HDL cholesterol and lipid accumulation in tissue macrophages. Several recent genome-wide association studies have identified common variants in ABCA1 as a significant source of variation in plasma HDL cholesterol levels across multiple ethnic groups, 2-4 establishing ABCA1 as a major gene influencing HDL levels in humans.Despite the known role of ABCA1 in determining plasma HDL levels, the impact of ABCA1 on atherosclerosis remains controversial and incompletely understood. TD patients have increased risk of coronary artery disease relative to related controls, 5,6 though perhaps not as great a risk as would be expected based on their extremely low HDL cholesterol levels. In contrast, a recent study suggested that low HDL caused by loss-of-function mutations in ABCA1 does not contribute to risk of cardiovascular disease in the general population. 7 Studies in mouse models have also yielded conflicting results. Mice lacking Abca1 globally exhi...