The Mechanism of the Remodeling of High Density Lipoproteins by Phospholipid Transfer Protein

Abstract

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...

Effects of Protein Oxidation on the Structure and Stability of Model Discoidal High-Density Lipoproteins

“…Remodeling of spherical lipoproteins into larger and smaller particles has been well-documented. For example, conversion of plasma HDL into larger and smaller particles occurs upon remodeling by plasma factors, such as phospholipid transfer protein (48), probably due to imbalance between the core and surface of spherical particles. Another example is heat-induced conversion of very low-density lipoproteins into larger and smaller spherical particles resulting in transient formation of small HDL-like lipoproteins (49).…”

Atheroprotective Potential of Macrophage-Derived Phospholipid Transfer Protein in Low-Density Lipoprotein Receptor-Deficient Mice Is Overcome by Apolipoprotein AI Overexpression

“…However, these studies were performed with plasma HDLs, and we published that PLTP requires triglyceride-rich HDLs to generate pre-␤-HDLs. 5 Further in vitro remodeling studies using triglyceride-rich HDLs are needed to better understand this process.…”

“…Cultured cells were plated at either 5ϫ10 5 or 1ϫ10 6 cells/mL and loaded with cholesterol using serum-free DMEM media containing 1% Nutridoma-SP, acetylated LDL (Intracell), and 5 mol/L 22-OH-cholesterol. Culture supernatants were collected after 4, 24, or 48 hours and PLTP activity determined as described above.…”

Recent advances in physiological lipoprotein metabolism

“…The mechanism of remodeling of HDL by PLTP is not fully understood. Studies with reconstituted HDL suggest that remodeling involves the formation of a large unstable fusion product, which either rearranges into small particles that is not accompanied by the dissociation of apoAI or loses molecules of apoAI to form a more stable, large conversion product [261]. It can be postulated that the small HDL and apoAI particles generated serve as acceptors for cell-derived cholesterol.…”