Plasma phospholipid transfer protein (PLTP) is thought to be involved in the remodeling of high density lipoproteins (HDL), which are atheroprotective. It is also involved in the metabolism of very low density lipoproteins (VLDL). Hence, PLTP is thought to be an important factor in lipoprotein metabolism and the development of atherosclerosis. We have overexpressed PLTP in mice heterozygous for the low density lipoprotein (LDL) receptor, a model for atherosclerosis. We show that increased PLTP activity results in a dose-dependent decrease in HDL, and a moderate stimulation of VLDL secretion (<1.5-fold). The mice were given a high fat, high cholesterol diet, which resulted in hypercholesterolemia in all animals. HDL concentrations were dramatically reduced in PLTP-overexpressing animals when compared with LDL receptor controls, whereas VLDL ؉ LDL cholesterol levels were identical. Susceptibility to atherosclerosis was increased in a PLTP doseresponsive manner. We conclude that PLTP increases susceptibility to atherosclerosis by lowering HDL concentrations, and therefore we suggest that an increase in PLTP is a novel, long term risk factor for atherosclerosis in humans. High density lipoproteins (HDL)1 are believed to be protective against the development of atherosclerosis because they mediate reverse cholesterol transport, i.e. the transfer of cholesterol from peripheral tissues to the liver (1, 2). However, our understanding of the molecular details and key regulatory proteins involved is incomplete (3-5). One effector of this process is the ATP-binding cassette ABCA1, which is functionally deficient in Tangier disease (reviewed in Ref. 6). The high incidence of coronary artery disease in Tangier patients suggests an essential, protective role of HDL-mediated reverse cholesterol transport in the development of atherosclerosis (7).However, recent results suggest that the contribution of ABCA1 to overall reverse cholesterol transport and its role in atherogenesis are primarily related to its function in macrophages (8 -10). Therefore, other potential key proteins in reverse cholesterol transport are of interest, including PLTP (11-13).Previously, we generated transgenic mice overexpressing human PLTP and showed that plasma from these animals is more effective in preventing accumulation of cholesterol by cultured macrophages (14). We and others therefore suggested an antiatherogenic effect for PLTP (14 -16). On the other hand, overexpression of PLTP results in a decrease of plasma HDL levels (14, 17, 18), which could be an atherogenic effect. Thus, it is unclear whether the net effect of high PLTP activity levels would be atherogenic or anti-atherogenic. The complete absence of PLTP activity in PLTP knockout mice inhibits HDL maturation, which results in reduced levels of plasma HDL caused by accelerated decay (19,20). Still, PLTP knockout mice showed decreased atherosclerosis (21). This could be partly explained by the discovery of a novel, intracellular function of PLTP in hepatocytes; it was found that PLTP def...

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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...

This study examined the role of cholesteryl ester transfer (CET), cholesteryl ester transfer protein (CETP) activity, and phospholipid transfer protein (PLTP) activity in the increased prevalence of coronary artery calcification (CAC) in diabetic subjects compared with nondiabetic subjects and in the loss of the sex difference in CAC in diabetes. CETP activity, PLTP activity, and CET were measured in 195 type 1 diabetic subjects without renal failure and 194 nondiabetic control subjects of similar age (30 -55 years) and sex distribution (50% female). CAC was quantified with electron beam computed tomography. CETP activity was higher in diabetic subjects (mean 84 arbitrary units [AU]) than in nondiabetic subjects (80 AU, P ‫؍‬ 0.028). PLTP activity was also higher in diabetic subjects (96 AU) than in nondiabetic subjects (81 AU, P < 0.001). However, CET was lower in diabetic men (geometric mean 32 nmol · ml -1 · h -1 ) than nondiabetic men (37 nmol · ml -1 · h -1 , P ‫؍‬ 0.004) and did not differ between diabetic (30 nmol · ml -1 · h -1 ) and nondiabetic (32 nmol · ml -1 · h -1 , P ‫؍‬ 0.3) women. CETP and PLTP activities were not associated with CAC. CET was positively associated with CAC in both diabetic and nondiabetic subjects (odds ratio per 10 nmol · ml -1 · h -1 increase in CET in all subjects ‫؍‬ 1.4, P ‫؍‬ 0.001). The prevalence of CAC was similar in diabetic (51%) and nondiabetic (54%, P ‫؍‬ 0.7) men but was much higher in diabetic (47%) than nondiabetic (21%, odds ratio 3.6, P < 0.001) women so that there was no sex difference in CAC in diabetic subjects. The odds of CAC in diabetic women compared with nondiabetic women was altered little by adjustment for CETP activity, PLTP activity, or CET (odds ratio on adjustment 3.7, P < 0.001). The greater effect of diabetes on CAC in women than in men, i.e., the loss of the sex difference in CAC, was independent of CETP and PLTP activity and CET. In conclusion, among both diabetic and nondiabetic subjects, higher cholesteryl ester transfer is a risk factor for CAC. However, abnormalities in cholesteryl ester transfer or lipid transfer protein activities do not underlie the increased CAC risk in diabetic women compared with nondiabetic women or the loss of the sex difference in CAC in diabetes.