Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of preβ-high-density lipoproteins

Abstract

High-density lipoproteins (HDLs) are considered anti-atherogenic because they mediate peripheral cell cholesterol transport to the liver for excretion and degradation. An important step in this reverse cholesterol-transport pathway is the uptake of cellular cholesterol by a specific subclass of small, lipid-poor apolipoprotein A-I particles designated pre beta-HDL. The two lipid-transfer proteins present in human plasma, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), have both been implicated in the formation of pre beta-HDL. In order to investigate the relative contribution of each of these proteins, we used transgenic mouse models. Comparisons were made between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice (huPLTPtg) and mice transgenic for both lipid-transfer proteins (huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP activity, PLTP activity or both activities, respectively. We evaluated the generation of pre beta-HDL in mouse plasma by immunoblotting and crossed immuno-electrophoresis. Generation of pre beta-HDL was equal in huCETPtg and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice, pre beta-HDL generation was 3-fold higher than in plasma from either wild-type or huCETPtg mice. Our findings demonstrate that, of the two plasma lipid-transfer proteins, PLTP rather than CETP is responsible for the generation of pre beta-HDL. These data support the hypothesis of a role for PLTP in the initial stage of reverse cholesterol transport.

Plasma phospholipid transfer protein activity, a determinant of HDL kinetics in vivo

“…Our observation that plasma PLTP was highly inversely associated with the LpA‐I subpopulation and not the LpA‐I:A‐II suggests that a lower PLTP activity is associated with selective increase in LpA‐I in our study population. This PLTP‐mediated redistribution may be beneficial in terms of cholesterol efflux from peripheral cells 35 . Hajj et al .…”

Macrophage PLTP is atheroprotective in LDLr-deficient mice with systemic PLTP deficiency

“…It is particularly important in the regulation of HDL populations, which have well-described antiatherogenic properties (10,11). PLTP can increase lipoprotein susceptibility to harmful oxidative damage by altering vitamin E distribution (12), yet it can beneficially improve cellular cholesterol efflux from peripheral tissues by increasing the rate of reverse cholesterol transport (13,14). In the latter pathway, HDL accepts excess cholesterol from peripheral tissues and transports it to the liver for secretion into bile (15).…”

Cholesteryl ester transfer protein: A potential target for the treatment of coronary artery disease

“…Although no net mass transfer of neutral lipids was initially observed between HDL and LDL, it is now well established that a net mass transfer of CE indeed occurs from HDL to LDL in human plasma. In addition, LDL particles of the intermediate size and density subclass appear to represent the preferential acceptors for CE among the major LDL subclasses 20 . Moreover, it is important to note that CETP can equally mediate exchange of neutral lipids between distinct HDL subspecies.…”