Two lipid transfer proteins are active in human plasma, cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). Mice by nature do not express CETP. Additional inactivation of the PLTP gene resulted in reduced secretion of VLDL and subsequently in decreased susceptibility to diet-induced atherosclerosis. The aim of this study is to assess possible effects of differences in PLTP expression on VLDL secretion in mice that are proficient in CETP and PLTP. We compared human CETP transgenic (huCETPtg) mice with mice expressing both human lipid transfer proteins (huCETPtg/huPLTPtg). Plasma cholesterol in huCETPtg mice was 1.5-fold higher compared with huCETPtg/huPLTPtg mice ( P Ͻ 0.001). This difference was mostly due to a lower HDL level in the huCETPtg/huPLTPtg mice, which subsequently could lead to the somewhat decreased CETP activity and concentration that was found in huCETPtg/huPLTPtg mice ( P Ͻ 0.05). PLTP activity was 2.8-fold increased in these animals ( P Ͻ 0.001). The human PLTP concentration was 5 g/ml. Moderate overexpression of PLTP resulted in a 1.5-fold higher VLDL secretion compared with huCETPtg mice ( P Ͻ 0.05). The composition of nascent VLDL was similar in both strains. These results indicate that elevated PLTP activity in huCETPtg mice results in an increase in VLDL secretion. In addition, PLTP overexpression decreases plasma HDL cholesterol as well as CETP. Phospholipid transfer protein (PLTP) is an important modulator of plasma HDL levels, size, and composition (1-5). HDL is considered to protect against atherosclerosis by transporting cellular cholesterol from cells in the arterial wall to the liver for further excretion via the bile, as well as by exerting anti-inflammatory and anti-oxidant effects (6-8).The role of PLTP in atherosclerosis was recently evaluated in PLTP deficient mice (5). PLTP deficiency in hyperlipidemic mouse models resulted in decreased atherosclerosis. In vitro experiments with cultured hepatocytes from PLTP deficient mice revealed a defect in VLDL secretion. These effects on VLDL secretion provided an explanation for the decreased atherosclerosis found in PLTP deficient mice (5).Earlier we reported anti-atherogenic properties in mice overexpressing human PLTP (huPLTPtg). Despite lower HDL levels, plasma from these mice is more effective in preventing in vitro accumulation of cholesterol by macrophages and is able to generate more pre ␤ -HDL (3, 9). Studies in mice with adenovirus-mediated overexpression of human PLTP showed similar effects on HDL subclass distribution (10, 11).Thus, depending on the metabolic setting, PLTP may have anti-or pro-atherogenic properties that require further investigation. Presently, we aimed to evaluate whether VLDL secretion is affected by variations in PLTP activity. For this purpose, we crossbred transgenic mice for human CETP (huCETPtg) with huPLTPtg mice (9) and obtained huCETPtg/huPLTPtg mice. These mice provide a unique model to study the role of PLTP in VLDL metabolism in the presence of CETP, whi...

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice have increased atherosclerosis. However, mice do not express cholesteryl ester transfer protein (CETP), which is involved in the same metabolic pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous LDL receptor-deficient (LDLR ؉ / ؊ ) mice expressing both human CETP and human PLTP. We used two transgenic lines with moderately and highly elevated plasma PLTP activity. In LDLR ؉ / ؊ /huCETPtg mice, cholesterol is present in both LDL and HDL. Both are decreased in LDLR ؉ / ؊ /huCETPtg/huPLTPtg mice ( Ͼ 50%). An atherogenic diet resulted in high levels of VLDL ؉ LDL cholesterol. PLTP expression caused a strong PLTP dosedependent decrease in VLDL and LDL cholesterol ( ؊ 26% and ؊ 69%) and a decrease in HDL cholesterol ( ؊ 70%). Surprisingly, atherosclerosis was increased in the two transgenic lines with moderately and highly elevated plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating that the adverse effect of the reduction in plasma HDL outweighs the beneficial effect of the reduction in apolipoprotein B (apoB)-containing lipoproteins. The activities of the antiatherogenic enzymes paraoxonase and platelet-activating factor acetyl hydrolase were both PLTP dose-dependently reduced ( ‫ف‬ ؊ 33% and ؊ 65%, respectively). We conclude that expression of PLTP in this animal model results in increased atherosclerosis in spite of reduced apoBcontaining lipoproteins, by reduction of HDL and of HDLassociated antioxidant enzyme activities. -Lie, J., R. Plasma levels of HDL are inversely correlated with the risk for development of atherosclerosis (1). HDLs are considered to have various atheroprotective effects, including anti-inflammatory and antioxidant properties and the potential to transport excess cholesterol from peripheral cells to the liver for degradation and excretion via the bile (1-4).Phospholipid transfer protein (PLTP) plays several key roles in HDL metabolism (5-8). PLTP facilitates the transfer of phospholipids, ␣ -tocopherol, and possibly unesterified cholesterol from triglyceride-rich lipoproteins to HDL particles during lipolysis (9, 10). PLTP is able to modulate HDL size and composition (11-13) and may also be involved in HDL cellular-mediated efflux of phospholipids and cholesterol (14).Elevation of PLTP in transgenic mice results in a PLTP dose-dependent decrease in plasma HDL levels, coinciding with an increased susceptibility to diet-induced atherosclerosis (15). These results are in agreement with the previous study by Jiang et al. (16), who demonstrated that PLTP-deficient mice are less prone to atherosclerosis. However, the explanations for the results were different in these cases; the changes in atherosusceptibility in PLTPdeficient mice were explained by a decrease of hepatic VLDL secretion, not by an HDL effect. Elevation of PLTP results in a stimulation of VLDL secretion (17), but this effect was found to be PL...

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 preβ-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 preβ-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 preβ-HDL in mouse plasma by immunoblotting and crossed immuno-electrophoresis. Generation of preβ-HDL was equal in huCETPtg and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice, preβ-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 preβ-HDL. These data support the hypothesis of a role for PLTP in the initial stage of reverse cholesterol transport.

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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.