Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice

Abstract

In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/ hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/ hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages.-Moerland, M., H. Samyn, T. van Gent, M. Jauhiainen, J. Metso, R. The incidence of coronary heart disease shows a strong inverse relationship with the concentration of plasma HDL (1). Therefore, HDL is believed to have antiatherogenic properties, which are attributed to its effects on endothelial cells, its antioxidant activity, and its role in reverse cholesterol transport, a pathway in which peripheral cellular cholesterol is transported to the liver (2-4). One important determinant of the plasma HDL concentration is phospholipid transfer protein (PLTP) activity. During lipolysis, PLTP transfers phospholipids from apolipoprotein Bcontaining lipoproteins to HDL (5). Furthermore, PLTP acts as an HDL conversion factor by remodeling HDL to produce large particles and small lipid-poor particles, known as preb-HDL (6-9). The latter HDL subfraction is a very efficient acceptor of cellular cholesterol. In this way, PLTP plays an important role in the early steps of reverse cholesterol transport (10-12).Although the involvement of PLTP in the cellular efflux of cholesterol and phospholipids is potentially antiatherogenic, different in vivo studies showed that an increase in plasma PLTP activity is associated with decreased HDL cholesterol levels (9, 13, 14) and increased atherosclerotic lesion development (15-17). The PLTP-dependent decrease in HDL levels was explained by an accelerated HDL catabolism (13). In addition to its effect on HDL cholesterol levels, PLTP may alter the antiathe...

Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models

“…Higher activity of CETP would facilitate transfer of HDLcholesterol to ApoB-containing lipoproteins, reducing the amount of cholesterol in HDL, reducing HDL particle size and increasing their capacity to accept new cholesterol from cells even when ApoB-containing lipoproteins are removed. This is consistent with several reports that smaller particles are more active in cholesterol efflux [40,41], and our recent finding of a correlation between the ability of plasma to support cholesterol efflux and CETP concentration [12]. It is, however, inconsistent with findings that functionality of HDL particles formed as a result of inhibition of CETP was not impaired [42,43].…”

Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

“…In the mutPLTP tg mice, the extent of atherosclerosis was comparable to that in the control littermates. In PLTP tg mice, however, increased atherosclerotic lesion sizes were found, consistent with earlier findings in mice overexpressing human PLTP (10,16). The presence of cholate in the diet has been shown to regulate PLTP gene expression in vivo by the nuclear farnesoid X receptor (FXR), because the PLTP promoter contains an FXR response element (35).…”

“…Furthermore, plasma PLTP has been identified as an HDL conversion factor. It remodels HDL to generate large particles and small lipid-poor preb-HDL (8)(9)(10). In vitro, HDL conversion depends on phospholipid transfer activity of PLTP (11).…”

Plasma lipid transfer proteins: The role of PLTP and CETP in atherogenesis

“…30 It has also been shown that RCT is less efficient in transgenic mice overexpressing PLTP, which may indicate that elevated levels of PLTP may promote atherogenesis by the accumulation of cholesterol in the blood vessel wall. 31 PLTP activity can be monitored by phospholipid carrying capacity from VLDL and LDL to HDL. PLTP activity is strongly correlated with the concentration of triglycerides in plasma and triglyceride content in HDL particles; this is probably due to the increased ability of phospholipid binding by HDL particles rich in triglycerides.…”