Lipid-loaded macrophage "foam cells" accumulate in the subendothelial space during the development of fatty streaks and atherosclerotic lesions. To better understand the consequences of such lipid loading, murine peritoneal macrophages were isolated and incubated with ligands for two nuclear receptors, liver X receptor (LXR) and retinoic acid receptor (RXR). Analysis of the expressed mRNAs using microarray technology led to the identification of four highly induced genes that encode apolipoproteins E, C-I, C-IV, and C-II. Northern blot analysis confirmed that the mRNA levels of these four genes were induced 2-14-fold in response to natural or synthetic ligands for LXR and/or RXR. The induction of all four mRNAs was greatly attenuated in peritoneal macrophages derived from LXR␣/ null mice. The two LXR response elements located within the multienhancers ME.1 and ME.2 were shown to be essential for the induction of apoC-II promoter-reporter genes by ligands for LXR and/or RXR. Finally, immunohistochemical studies demonstrate that apoC-II protein co-localizes with macrophages within murine arterial lesions. Taken together, these studies demonstrate that activated LXR induces the expression of the apoE/C-I/C-IV/C-II gene cluster in both human and murine macrophages. These results suggest an alternative mechanism by which lipids are removed from macrophage foam cells.
Vitamin E is a lipophilic anti-oxidant that can prevent the oxidative damage of atherogenic lipoproteins. However, human trials with vitamin E have been disappointing, perhaps related to ineffective levels of vitamin E in atherogenic apoB-containing lipoproteins. Phospholipid transfer protein (PLTP) promotes vitamin E removal from atherogenic lipoproteins in vitro, and PLTP deficiency has recently been recognized as an antiatherogenic state. To determine whether PLTP regulates lipoprotein vitamin E content in vivo, we measured ␣-tocopherol content and oxidation parameters of lipoproteins from PLTP-deficient mice in wild type, apoEdeficient, low density lipoprotein (LDL) receptor-deficient, or apoB/cholesteryl ester transfer protein transgenic backgrounds. In all four backgrounds, the vitamin E content of very low density lipoprotein (VLDL) and/or LDL was significantly increased in PLTP-deficient mice, compared with controls with normal plasma PLTP activity. Moreover, PLTP deficiency produced a dramatic delay in generation of conjugated dienes in oxidized apoB-containing lipoproteins as well as markedly lower titers of plasma IgG autoantibodies to oxidized LDL. The addition of purified PLTP to deficient plasma lowered the vitamin E content of VLDL plus LDL and normalized the generation of conjugated dienes. The data show that PLTP regulates the bioavailability of vitamin E in atherogenic lipoproteins and suggest a novel strategy for achieving more effective concentrations of antioxidants in lipoproteins, independent of dietary supplementation.The oxidation theory of atherogenesis has received wide support from a number of different lines of evidence (1, 2). In particular, treatment of hypercholesterolemic animals with a variety of potent synthetic anti-oxidants has resulted in inhibition of the progression of atherosclerosis (3). However, a direct relationship between the susceptibility of LDL 1 to oxidation and the extent of atherosclerosis has not been found in all studies, and attempts to prevent atherogenesis by feeding diets enriched in "natural" anti-oxidants have provided mixed and sometimes disappointing results (2, 3). Recently, it was shown that feeding large doses of vitamin E to apoE-deficient mice decreased the progression of atherosclerosis (4, 5). However, with a few exceptions (6, 7), the administration of vitamin E in human trials has been negative (8 -12). An important issue that has not been addressed in such studies is the actual concentrations of vitamin E in atherogenic lipoproteins. Recently, mice with ␣-tocopherol transfer protein deficiency were shown to have reduced vitamin E content in lipoproteins, and moderately increased susceptibility to atherosclerosis (13). However, little is known of the physiological mechanism regulating the turnover and levels of vitamin E in the plasma lipoproteins.The plasma phospholipid transfer protein (PLTP) mediates both net transfer and exchange of phospholipids between lipoproteins (14). PLTP can also bind and transfer several other amphipathic lipids, ...
Vitamin E supplementation constitutes a promising strategy in the prevention of neurodegenerative diseases. Here, we show that a phospholipid transfer protein (PLTP) is widely expressed in the brain where it appears to function as a transfer factor for alpha-tocopherol, the main isomer of vitamin E. PLTP deficiency results in significant depletion of brain alpha-tocopherol in both homozygous (-30.1%, P<0.0002) and heterozygous (-18.0%, P<0.05) PLTP knocked-out mice. Alpha-tocopherol depletion in PLTP-deficient homozygotes is associated with the elevation of lipofuscin (+25% and +450% increases in cortex and substantia nigra, respectively), cholesterol oxides (+54.5%, P<0.05), and cellular peroxides (+32.3%, P<0.01) in the brain. Complete PLTP deficiency in homozygotes is accompanied by increased anxiety as shown by fewer entries (8.3% vs. 44.4% in controls, P<0.01) and less time spent (1.7% vs. 41.3% in controls, P<0.05) in the open arms of an elevated plus-maze, in the absence of locomotor deterioration. Thus, the vitamin E transfer activity of PLTP appears to be a key process in preventing oxidative damage in the brain, and PLTP-deficient mice could be a new model of the contribution of oxidative brain injury in the etiology of neurodegenerative diseases.
Vitamin E is composed of closely related compounds, including tocopherols and tocotrienols. Studies of the last decade provide strong support for a specific role of alpha-tocopherol in cell signalling and the regulation of gene expression. It produces significant effects on inflammation, cell proliferation and apoptosis that are not shared by other vitamin E isomers with similar antioxidant properties. The different behaviours of vitamin E isomers might relate, at least in part, to the specific effects they exert at the plasma membrane. alpha-Tocopherol is not randomly distributed throughout the phospholipid bilayer of biological membranes, and as compared with other isomers, it shows a propensity to associate with lipid rafts. Distinct aspects of vitamin E transport and metabolism is discussed with emphasis on the interaction between alpha-tocopherol and lipid rafts and the consequences of these interactions on cell metabolism.
Abstract-Mean plasma phospholipid transfer protein (PLTP) concentrations were measured for the first time by using a competitive enzyme-linked immunosorbent assay. PLTP mass levels and phospholipid transfer activity values, which were significantly correlated among normolipidemic plasma samples (rϭ0.787, PϽ0.0001), did not differ between normolipidemic subjects (3.95Ϯ1.04 mg/L and 575Ϯ81 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ30), type IIa hyperlipidemic patients (4.06Ϯ0.84 mg/L and 571Ϯ43 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ36), and type IIb hyperlipidemic patients (3.90Ϯ0.79 mg/L and 575Ϯ48 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ33). No significant correlations with plasma lipid parameters were observed among the various study groups. In contrast, plasma concentrations of the related cholesteryl ester transfer protein (CETP) were higher in type IIa and type IIb patients than in normolipidemic controls, and significant, positive correlations with total and low density lipoprotein cholesterol levels were noted. Interestingly, plasma PLTP mass concentration and plasma phospholipid transfer activity were significantly higher in patients with non-insulin-dependent diabetes mellitus (nϭ50) than in normolipidemic controls (6.76Ϯ1.93 versus 3.95Ϯ1.04 mg/L, PϽ0.0001; and 685Ϯ75 versus 575Ϯ81 nmol ⅐ mL, PϽ0.0001, respectively). In contrast, CETP levels did not differ significantly between the 2 groups. Among non-insulin-dependent diabetes mellitus patients, PLTP levels were positively correlated with fasting glycemia and glycohemoglobin levels (rϭ0.341, Pϭ0.0220; and rϭ0.382, Pϭ0.0097, respectively) but not with plasma lipid parameters. It is proposed that plasma PLTP mass levels are related to glucose metabolism rather than to lipid metabolism. Key Words: cholesteryl ester transfer protein Ⅲ lipid transfer Ⅲ ELISA Ⅲ glucose Ⅲ non-insulin-dependent diabetes mellitus I n vivo, plasma lipoproteins do not constitute stable entities but are continuously remodeled through the action of several enzymes and lipid transfer proteins. In particular, cholesteryl ester transfer protein (CETP) 1 and phospholipid transfer protein (PLTP), 2 related proteins belonging to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family, 1 can promote the exchange of lipid species between various plasma lipoprotein fractions. In fact, studies over the past few years have demonstrated that both CETP and PLTP produce multiple effects on lipoprotein structure and composition. Thus, CETP promotes the exchange of neutral lipids, ie, CEs and triglycerides, between plasma lipoprotein fractions, leading to alterations in both the neutral lipid content and the size distribution of lipoproteins. 2,3 PLTP can facilitate the transfer of phospholipids between lipoprotein particles, 4 and it was lately shown to transfer lipopolysaccharides, 5 unesterified cholesterol, 6 and ␣-tocopherol 7 as well. In addition, PLTP constitutes an important determinant of the size distribution of HDL. 3,8 -12 Taken together, recent advances have raised considerab...
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