Impact of Phospholipid Transfer Protein on Nascent High-Density Lipoprotein Formation and Remodeling

Abstract

Objective Phospholipid transfer protein (PLTP), which binds phospholipids and facilitates their transfer between lipoproteins in plasma, plays a key role in lipoprotein remodeling but its influence on nascent HDL formation is not known. The effect of PLTP over-expression on apoA-I lipidation by primary mouse hepatocytes was investigated. Approach and Results Over-expression of PLTP through an adenoviral vector markedly affected the amount and size of lipidated apoA-I species that were produced in hepatocytes in a dose-dependent manner, ultimately generating particles that were smaller than 7.1 nm but larger than lipid-free apoA-I. These < 7.1 nm small particles generated in the presence of over-expressed PLTP were incorporated into mature HDL particles more rapidly than apoA-I both in vivo and in vitro, and were less rapidly cleared from mouse plasma than lipid-free apoA-I. The < 7.1 nm particles promoted both cellular cholesterol and phospholipid efflux in an ATP-binding cassette transporter A1 (ABCA1) dependent manner, similar to apoA-I in the presence of PLTP. Lipid-free apoA-I had a greater efflux capacity in the presence of PLTP than in the absence of PLTP, suggesting that PLTP may promote ABCA1-mediated cholesterol and phospholipid efflux. These results indicate that PLTP alters nascent HDL formation by modulating the lipidated species as well as promoting the initial process of apoA-I lipidation. Conclusions Our findings suggest that PLTP exerts significant effects on apoA-I lipidation and nascent HDL biogenesis in hepatocytes by promoting ABCA1-mediated lipid efflux and the remodeling of nascent HDL particles.

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

“…The composition, size and structure of ABCA1-derived nHDL 6,7 as well as the metabolism of nHDL-protein derived from several cell types, including macrophage foam cells, have been reported and are similar. 18,28,29 Cell-ABCA1-derived nHDL is both similar and different from human plasma pre-β HDL. Both contain FC, PL and apo AI.…”

HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity

“…We have previously shown that, within the time frame of the HAE assay, lipid-free apoA-I predominantly exchanges onto smaller HDL particles ( 31 ). Furthermore, in vitro studies of HDL remodeling in the absence of apoB particles catalyzed by LCAT ( 42,43 ), PLTP ( 44,45 ), or effl ux capacity included HAE, gender, age, HDL-C, triglycerides, and statin use, and explained over 80% of the J774 effl ux variance, with HDL-C ( b = 0.884, P < 0.0001, 59% model variance explained) and HAE ( b = 0.202, P = 0.031, 26% model variance explained) as the most signifi cant contributors to the model ( Table 3 ). The model for ABCA1-specifi c effl ux capacity explained over 50% of the variance, with HAE as the strongest predictor ( b = 0.342, P = 0.015, 24% explained) followed by HDL-C ( b = 0.390, P = 0.01, 23% explained).…”

Is ABCA1 a lipid transfer protein?

“…The increased efflux upon SM depletion is due, at least in part, to increased levels of PS in the exofacial leaflet of the PM; this redistribution is due to impaired inward PS translocation upon SM depletion (95). The effect of PL transfer protein (PLTP) is an example of a factor in the extracellular medium that influences ABCA1 activity; PLTP interacts with ABCA1 and stabilizes it (96) thereby promoting ABCA1-mediated FC and PL efflux as well as nascent HDL particle remodeling (97).…”