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Objective-Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI. Methods and Results-Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLrϪ/Ϫ) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks. Macrophage PLTP deficiency increased atherosclerosis in LDLrϪ/Ϫ mice with minimal changes in total plasma cholesterol levels. In contrast, the extent of atherosclerosis in msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg mice was not significantly different between groups that had received PLTPϪ/Ϫ or PLTPϩ/ϩ bone marrow. In vitro studies indicated that PLTP deficiency led to a significant decrease in ␣-tocopherol content and increased oxidative stress in bone marrow cells. Key Words: phospholipid transfer protein Ⅲ apolipoprotein AI Ⅲ atherosclerosis Ⅲ transgenic mice Ⅲ bone marrow transplant P hospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in phospholipid and vitamin E transfers among plasma lipoproteins as well as between lipoproteins and cell membranes. [1][2][3] In addition, PLTP participates in the formation of pre-␤-highdensity lipoproteins (HDLs) that promote the efflux of excess cellular cholesterol 4 -6 via the ATP-binding cassette transporter A1 (ABCA1) pathway. 7 Recent in vivo studies of PLTP transgenic and PLTP knockout mice report that PLTP plays a role in the control of plasma levels of both HDLs and apolipoprotein B (apoB)-containing lipoproteins. 8 -11 Systemic PLTP deficiency is atheroprotective in different strains of hypercholesterolemic mice, and transgenic mice overexpressing human PLTP have an increased risk of atherosclerosis. 9,12,13 To further support a proatherogenic potential of plasma PLTP in vivo, a positive correlation between circulating PLTP and the risk of coronary artery disease is observed in humans. 14 These studies have emphasized the action of PLTP at the systemic level and suggest that its proatherogenicity is likely a result of its actions on circulating lipoproteins. Although the impact of systemic PLTP on lipoprotein metabolism and antioxidant potential was studied, its tissue-specific actions have not been addressed. Conclusions-OurPLTP is synthesized and secreted by most cell types in humans and mice, and although first described as a plasma protein, it was recently shown to be expressed in macrophages within the intima of human atherosclerotic arteries. 15 We and others reported that PLTP is synthesized and secreted by cultured macrophages, and that the gene is upregulated by liver X receptor (LXR) ligands. 15,16 Macrophages are ess...

Daily consumption of this new DS decreased LDL-cholesterol and TC and is therefore an interesting, convenient aid in managing mild to moderate hypercholesterolemia.

The NCLS was effective in reducing low-density lipoprotein cholesterol and apolipoprotein B100 in subjects with moderate hypercholesterolemia, without modifying safety parameters.

Objective-Phospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in lipoprotein metabolism and atherosclerosis. Recent in vivo studies suggested that unlike systemic PLTP, macrophage-derived PLTP would be antiatherogenic. The present study aimed at characterizing the atheroprotective properties of macrophage-derived PLTP. Methods and Results-Peritoneal macrophages were isolated from PLTP-deficient and wild-type mice and their biochemical characteristics were compared. It is shown that macrophages isolated from PLTP-deficient mice have increased basal cholesterol content and accumulate more cholesterol in the presence of LDL compared with wild-type cells. Cholesterol parameters in macrophages of PLTP-deficient mice were normalized by dietary ␣-tocopherol supplementation. Key Words: phospholipid transfer protein Ⅲ vitamin E Ⅲ tocopherol Ⅲ macrophage P hospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in lipoprotein metabolism and atherosclerosis. [1][2][3][4] In addition to phospholipids, PLTP transfers several amphipatic compounds including unesterified cholesterol, lipopolysaccharides, diacylglycerides, and ␣-tocopherol, the main isomer of vitamin E. 5-7 PLTP is produced by a variety of tissues and secreted by macrophages, the hallmark cells of atherosclerotic lesions. 8 -11 Several recent studies indicated that PLTP not only affects plasma lipid and lipoprotein profiles, but also modulates cell physiology. [12][13][14][15][16] To date, the question of the pro-or antiatherogenicity of PLTP has not been fully elucidated. On the one hand, recent in vivo studies indicated that systemic PLTP deficiency is atheroprotective in different strains of hypercholesterolemic mice, and sustained overexpression of plasma PLTP in PLTP transgenic or bone marrow-transplantated mice leads to an increased risk of atherosclerosis. [17][18][19][20][21] In further support of the proatherogenic potential of plasma PLTP in vivo, a positive correlation between PLTP activity and the risk of coronary artery disease was observed in humans. 22 On the other hand, recent observations from our group 23 as well as from Liu et al 24 indicated that the onset of atherosclerosis is significantly delayed in low density lipoprotein-receptor-deficient and apoEdeficient mice that were reconstituted with PLTP-expressing compared with PLTP-deficient (PLTP Ϫ/Ϫ ) bone marrow cells. In these experiments, PLTP expression was mostly restricted to macrophages with only minimal modification of plasma PLTP level, suggesting that unlike systemic PLTP, macrophage-derived PLTP would be atheroprotective in vivo. In other words, the consequences of PLTP on atherosclerosis in experimental models would result from a combination of antiatherogenic effect of macrophage PLTP and proatherogenic effect of systemic plasma PLTP. To assess selectively the impact of macrophage-derived PLTP on cell properties or cholesterol accumulation, periton...

Objective-Cholesteryl ester transfer protein (CETP) is a target gene for the liver X receptor (LXR). The aim of this study was to further explore this regulation in the monocyte-macrophage lineage and its modulation by lipid loading and inflammation, which are key steps in the process of atherogenesis. Methods and Results-Exposure of bone marrow-derived macrophages from human CETP transgenic mice to the T0901317 LXR agonist increased CETP, PLTP, and ABCA1 mRNA levels. T0901317 also markedly increased CETP mRNA levels and CETP production in human differentiated macrophages, whereas it had no effect on CETP expression in human peripheral blood monocytes. In inflammatory mouse and human macrophages, LXR-mediated CETP gene upregulation was inhibited, even though ABCA1, ABCG1, and SREBP1c inductions were maintained. The inhibition of CETP gene response to LXR agonists in inflammatory cells was independent of lipid loading (ie, oxidized LDL increased CETP production in noninflammatory macrophages with a synergistic effect of synthetic LXR agonists). Conclusion-LXR-mediated induction of human CETP expression is switched on during monocyte-to-macrophage differentiation, is magnified by lipid loading, and is selectively lost in inflammatory macrophages, which suggests that inflammatory cells may not increase the circulating CETP pool on LXR agonist treatment. Key Words: liver X receptor Ⅲ cholesteryl ester transfer protein Ⅲ macrophage Ⅲ monocyte Ⅲ inflammation M acrophages play a central role in the formation of atherosclerotic lesions. These cells produce the cholesteryl ester transfer protein (CETP), which accounts for the enrichment of circulating apoB-containing lipoproteins with cholesteryl esters, but can also contribute to reverse cholesterol transport. 1 As shown by bone marrow transplantation experiments in mice, macrophages, including liver macrophages (Kuppfer cells), contribute significantly to plasma CETP and PLTP pools. 2-5 CETP mRNA was identified mainly in nonparenchymal sinusoidal cells of the liver in cynomolgus monkeys. 6 In humans, cholesterol transfer activity was observed in the culture supernatant of human macrophages, 7,8 and CETP was localized in macrophagederived foam cells by immunohistochemistry or in situ hybridization analysis of atherosclerotic lesions. 9,10 CETP produced in the vicinity of the vascular bed may prevent cholesterol accumulation in lesion macrophages, 9,11 an event involved in both early and late stages of the disease. 12 However, under unfavorable conditions (eg, when apoB-containing lipoprotein clearance is defective), the deleterious effect of systemic CETP could overcome this local beneficial effect. Accordingly, hyperlipidemic LDLr-KO mice transplanted with CETP transgenic (CETPTg) bone marrow cells display a proatherogenic plasma lipoprotein profile and accelerated development of atherosclerotic lesions. 2 The CETP gene promoter can be transactivated in vitro and in vivo by liver X receptors (LXR). 13,14 These oxysterol-activated nuclear receptors interact with a DR4...

For the first time, this work reports a physiological role for PLTP in the polarization of CD4 T cells toward the pro-inflammatory Th1 phenotype.