内源性高甘油三酯血症患者血浆VLDL、LDL及HDL对血凝的影响

目的：研究内源性高甘油三酯血症(HTG)患血浆极低密度脂蛋白(VLDL)、低密度脂蛋白(LDL)及高密度脂蛋白(HDL)是否发生了氧化修饰及其对血凝的影响。方法：对2l例内源性高甘油三酯血症患与2l例年龄性别相近的正常人的血脂、脂质过氧化物进行了分析。用一次性密度梯度超速离心法分离血浆VLDL、LDL及HDL，测定这三种脂蛋白的234nm光吸收、相对电泳迁移率(REM)和硫代巴比妥酸反应物质(TBARS)，分别将这三种脂蛋白加入由正常人新鲜混合血浆构成的反应系统中，按试剂盒分别测定凝血酶原时间(PT)及活化部分凝血酶原时间(APIT)。结果：内源性HTG患血浆TG含量平均升高2．73倍，HDLC下降l.7l倍，同时LPO升高1．22倍;HTG组VLDL、LDL及HDL的REM、234nm光吸收值、TBARS含量均较对照组显增加(P＜0．01)，表明内源性HTG患血浆VLDL、LDL及LDL均发生了氧化修饰生成Ox—VLDL、Ox-LDL.PT及APTT在分别加入HTG组的VLDL、LDL及HDL后均比加入相应正常组脂蛋白明显缩短(P均＜0．05)。相关分析表明，HTG组血浆VLDL及HDL相对电泳迁移率(REM)与PT呈负相关(P＜0．01)。结论：HTG患血浆VLDL、LDL及HDL发生了氧化修饰，并使PT及APTT明显缩短。     

1-磷酸鞘氨醇通过提高心脏微血管密度缓解压力负荷诱导的小鼠心力衰竭

目的：探究1-磷酸鞘氨醇（sphingosine-1-phosphate, S1P）通过调节心脏微血管密度对压力负荷诱导的小鼠心力衰竭的作用及相关机制。方法：将8周龄的雄性C57BL/6小鼠随机分为4组：假手术（sham）组、sham+2-乙酰基-5-四羟基丁基咪唑（2-acetyl-5-tetrahydroxybutyl imidazole, THI; S1P裂解酶抑制剂）组、主动脉弓缩窄术（transverse aortic constriction, TAC）组和TAC+THI组。TAC手术后1周给予THI灌胃处理，实验终点检测各组小鼠血浆和心脏匀浆组织中S1P水平；心脏超声和Millar导管检测心功能；HE染色检测各组小鼠心脏肥大程度，Masson染色观察各组小鼠心脏间质和管周纤维化程度，CD31和麦胚凝集素免疫荧光染色观察各组小鼠心肌细胞横截面积和心脏微血管密度；RT-qPCR检测心房钠尿肽（atrial natriuretic peptide, ANP）、脑钠肽（brain natriuretic peptide, BNP）、I型胶原蛋白（collagen type I）、...     

脂蛋白相关磷脂酶A2对预测冠心病事件的临床价值

目的：探讨脂蛋白相关磷脂酶A2（Lp-PLA2）对预测国人冠心病（CHD）事件的临床价值。方法：通过检测108例CHD患者、40例健康体检者血液中Lp-PLA2、低密度脂蛋白胆固醇（LDL）的含量情况。结果：急性心肌梗死（AMI）组、不稳定型心绞痛（UAP）组、稳定型心绞痛（SAP）组和对照组,各组间Lp-PLA2、LDL含量呈现明显的梯度差异（均P〈0.05）。经线性相关分析,血浆Lp-PLA2与LDL水平呈正相关（P〈0.05）。结论：Lp-PLA2可作为国人的CHD事件的独立预测因子;血浆Lp-PLA2与LDL含量密切相关。     

脂质转运和脂酶水解对低密度脂蛋白的修饰作用

采用胆固醇脂转运蛋白（CETP）介导极低密度脂蛋白（VLDL）中甘油三酯（TG）与低密度脂蛋白（LDL）中胆固醇（CH）交换：再行脂蛋白脂酶（LPL）水解LDL中TG，对LDL进行修饰，引起LDL颗粒组成和大小的变化，探讨体内小而致密的LDL形成的可能途径，及易于致动脉粥样硬化（As）作用的机制。结果示CETP介导的脂质转运使LDL中TG含量增加，CH降低，颗粒直径轻微变大；再经LPL水解的共同作用，LDL中TG含量降低，颗粒变小。同时LDL中载脂蛋白B（apoB）免疫反应性也发生相应的变化，LDL中TG含量同apoB免疫反应性高度负相关。认为大而轻的A型LDL经修饰作用可转变为小而致密的B型LDL，富含TG的LDL不易于通过apoB受体途径清除，史易于氧化。     

载脂蛋白A5基因多态性与甘油三酯代谢及冠心病关系的研究进展

近年通过比较小鼠和人的基因组序列发现的载脂蛋白A5（Apolioprotein A5，ApoA5）是第一个过度表达引起血浆甘油三酯（TG）下降的载脂蛋白。除LDL颗粒外，CM、VLDL和HDL颗粒均含有ApoA5。ApoA5在血浆中含量甚微，其浓度仅为ApoA1的0．1％。小鼠基因敲除和基因导入实验表明ApoA5在调节血浆TG代谢方面起至关重要的作用，二者之间呈负相关。现对其分子结构、生物学功能、基因表达及调控作简要介绍，并着重讨论其基因多态性与血脂代谢和冠心病之间的关系。     

66例脑梗死患者血浆血脂分析和Hcy测定的临床应用

目的：探讨脑梗死患者血脂和同型半胱氨酸（Hcy）分析的临床意义。方法：生化法和化学发光免疫分析了66例脑梗死和58例正常对照组血浆中总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL—C）、高密度脂蛋白胆固醇（HDL—C）和同型半胱氨酸（Hcy）水平。结果：66例脑梗死患者较之58例正常对照组血浆TC、TG、LDL—C和Hcy显著增高（P均〈0．05和〈0．01）,而HDL—C显著降低（P〈0．05）。结论：血浆TC、TG、LDL—C、HDL—C和Hcy与脑梗死密切相关,并具有诊断和治疗随访的临床价值。     

急性脑梗死患者治疗前后临床血清学变化

目的探讨急性脑梗死患者治疗前后血清高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、血浆血栓素B2(TXB2),6-酮-前列腺素F1α(6-K-PGF1α)、甘油三脂(TG)、β脂蛋白(β-LP)的变化。方法对94例急性脑梗死患者(男58例,女36例),用放射免疫和生化方法检测血样本中HDL、LDL、TXB2、6-K-PGF1α、TG、β-LP的含量。结果急性脑梗死患者治疗后HDL、6-K-PGF1α浓度明显升高(P0.05),LDL、TG、β-LP、TXB2浓度显著降低(P0.01)。结论急性脑梗死患者治疗后血液的高凝状态明显改变,血脂降低。     

APP/PS1双转基因AD小鼠早期内质网应激诱导的凋亡

目的观察APP/PS1双转基因AD小鼠神经细胞凋亡,及内质网分子伴侣葡萄糖调节蛋白（GRP78）和内质网促凋亡因子半胱氨酸蛋白酶-12（Caspase-12）表达的改变,探讨APP/PS1双转基因AD小鼠早期内质网应激诱导的凋亡。方法选取5、7月龄的APP/PS1双转基因小鼠和同月龄同背景的野生型小鼠（WT）,分为5月龄WT组、5月龄APP/PS1组、7月龄WT组和7月龄APP/PS1组,每组6只,应用原位细胞凋亡检测法（TUNEL）检测凋亡细胞,免疫组织化学方法检测其脑内GRP78和Caspase-12的表达水平。结果 TUNEL检测凋亡率分别为7月龄APP/PS1鼠（35.0±6.31）%、5月龄APP/PS1鼠（9.0±2.78）%、7月龄WT鼠（4.0±1.89）%、5月龄WT鼠（4.0±1.83）%,其中7月龄APP/PS1鼠凋亡率显著升高（P〈0.05）;免疫组织化学检测GRP78阳性率分别为7月龄APP/PS1鼠（30.0±5.43）%、5月龄APP/PS1鼠（10.0±2.12）%、7月龄WT鼠（2.0±1.71）%、5月龄WT鼠（3.0±1.41）%,7月龄APP/PS1鼠GRP78表达明显升高（P〈0.05）;免疫组织化学检测Caspase-12阳性率分别为7月龄APP/PS1鼠（33.0±5.98）%、5月龄APP/PS1鼠（12.0±2.60）%、7月龄WT鼠（4.0±2.56）%、5月龄WT鼠（2.0±1.79）%,7月龄APP/PS1鼠Caspase-12表达明显升高（P〈0.05）。结论 7月龄的APP/PS1双转基因小鼠出现了内质网应激诱导的凋亡。本实验结果为临床AD早期预防和治疗提供了重要依据。     

α-突触核蛋白磷酸化参与小鼠多巴胺能神经元的保护作用

目的　研究α-突触核蛋白(α-SYN) 129位点磷酸化修饰是否具有神经元保护作用。方法　应用反转录病毒感染小鼠多巴胺能神经元细胞MN9D,通过实时定量PCR检测各组细胞内α-SYN过表达情况,并通过免疫细胞化学方法检测野生型α-SYN (WT/α-SYN)及129位点磷酸化α-SYN (S129D/α-SYN)过表达后α-SYN在细胞内聚集情况,应用CCK-8检测细胞活力,观察WT/α-SYN及S129D/α-SYN对MN9D的细胞毒性,从而明确S129D/α-SYN对多巴胺能神经元的影响。 结果　实时定量PCR结果显示,WT/α-SYN及S129D/α-SYN在MN9D细胞内均过表达（P<0.01）。WT/α-SYN过表达组细胞活力明显下降（P<0.01）,共聚焦显微镜观察未见明显的α-SYN聚集;S129D/α-SYN过表达组细胞内可观察到明显的α-SYN聚集体,同WT/α-SYN组相比细胞活力有明显提高（P<0.01）。结论　129位点丝氨酸的磷酸化修饰在一定程度上减轻了WT/α-SYN过表达所引起的细胞毒性。     

脂蛋白和C反应蛋白对单核细胞趋化蛋白-1的影响

目的探讨单核细胞趋化蛋白-1（MCP-1）及其受体趋化因子受体2（CCR-2）经动脉粥样硬化相关因素刺激后表达量的变化情况。方法密度梯度离心法从健康成人外周血中分离获得单个核细胞，体外培养48h。给予氧化低密度脂蛋白（ox-LDL）、C反应蛋白（CRP）及高密度脂蛋白（HDL）进行干预。干预后用实时荧光定量RT—PCR技术检测单核细胞MCP-1 mRNA和CCR2 mRNA的含量，ELISA法检测MCP-1蛋白含量。结果ox—LDL＋CRP组、ox—LDL、CRP处理组MCP-1和CCR2 mRNA表达水平和MCP—1蛋白含量明显高于对照组（P〈0．05）。而经HDL处理的单核细胞表达MCP-1和CCR2 mRNA水平下调，MCP-1蛋白含量低于对照组（P〈0．05）。结论在体外培养的条件下，CRP和ox-LDL可以促进MCP-1和CCR2 mRNA表达，继而导致MCP-1含量增加，增强炎症反应的范围和强度。HDL可以有效的抑制MCP-1的表达。     

Human seminal plasma displays significant phospholipid transfer activity due to the presence of active phospholipid transfer protein

The lipid composition of germ cell membranes is considerably modified during spermatogenesis, sperm maturation and capacitation. Some of these modifications are caused by exchanges between soluble lipid donors or acceptors and cell membranes. The aim of this study was to assess whether significant lipid transfers between lipoprotein structures are detectable in human seminal plasma. Phospholipid and cholesteryl ester (CE) transfer activities were measured by specific fluorescence and isotopic assays. Seminal plasma samples did not display significant CE transfer. Substantial levels of phospholipid transfer activity were detected in all samples studied, levels were approximately 25% of the phospholipid transfer activity measured in human blood plasma. Concordantly, CE transfer protein was not detected in seminal plasma, while the presence of the phospholipid transfer protein (PLTP) was confirmed by Western blot analysis. Enzyme-linked immunosorbent assay indicated that seminal PLTP concentrations represented 25% of the concentration measured in blood plasma. Blockade of phosphatidylcholine and phosphatidyl-ethanolamine transfer by a 60 min, 56 degrees C heating step or with anti-PLTP antibody revealed that PLTP accounts for almost 80% of the phospholipid transfer activity present in seminal plasma. As shown by gel-permeation chromatography and Western blot analysis, seminal PLTP activity was partially associated with prostasomes. Significantly higher PLTP activity levels were measured in seminal plasma samples with low seminal vesicle secretions. The latter observation may reflect the sustained secretion of active PLTP that is diluted in a variable volume of PLTP-free seminal vesicle secretion. In conclusion, human seminal plasma displays significant phospholipid transfer activity due to the presence of active PLTP.     

3,4,5,6-四羟基(口山)酮抑制ApoE基因缺陷小鼠动脉粥样硬化形成及机制

目的：研究3,4,5,6-四羟基口山酮抑制ApoE基因缺陷小鼠动脉粥样硬化(AS)形成的机制及其与内源性一氧化氮合酶(NOS)抑制剂非对称性二甲基精氨酸(ADMA)的关系。方法：32只小鼠分为4组(n=8):正常对照组(C57BL/6J小鼠，等体积溶媒灌胃)；模型组(ApoE基因缺陷小鼠，等体积溶媒灌胃)；低剂量口山酮组［ApoE基因缺陷小鼠，口山酮10mg/（kg·d）灌胃］；高剂量口山酮组［ApoE基因缺陷小鼠，口山酮20mg/（kg·d）灌胃］；检测主动脉脂质斑块面积、血脂、红细胞变形性和血浆ADMA的水平。结果：与模型组比较，口山酮可以显著降低血浆ADMA水平和斑块面积，降低血浆总胆固醇(TC)、血浆总甘油三酯(TG)、血浆低密度胆固醇(LDL-C)，显著升高血浆高密度胆固醇(HDL-C)和改善红细胞变形性。结论：3,4,5,6-四羟基口山酮具有抗AS作用, 其作用机制与改善脂质代谢和降低血浆ADMA的水平有关。     

apoE/LDLR双基因突变小鼠肝脏脂代谢相关基因的表达研究

目的探讨载脂蛋白E和低密度脂蛋白受体双基因缺失（apoE^-/-/LDLR^-/-）小鼠肝脏脂代谢相关基因表达特征与动脉粥样硬化早期病变的关系及发生机制。方法应用RT-PCR技术检测apoE^-/-／LDLR^-/-与野生型小鼠肝脏脂代谢相关基因表达差异,并进行血生化指标检测及主动脉形态学观察。结果所检测的11个脂代谢相关基因中,apoE^-/-／LDLR^-/-小鼠与野生型小鼠相比,载脂蛋白B100和脂肪酸转运体（FAT／CD36）的mRNA水平从14天龄至3月龄均升高。载脂蛋白AⅣ、载脂蛋白AⅤmRNA水平分别于14天龄和3月龄时明显降低。载脂蛋白AⅠ、载脂蛋白F、过氧化物增殖物激活型受体α、肝X受体α、血管生成素样蛋白3、酰基辅酶A氧化酶1及肉碱棕榈酰转移酶ImRNA表达水平无明显差异。血清总胆固醇、总甘油三酯和低密度脂蛋白胆固醇水平分别高于同龄野生型小鼠约7、2和30倍。随年龄增长apoE^-/-／LDLR^-/-小鼠主动脉内膜出现典型的动脉粥样硬化早期病变。结论上述脂代谢相关基因表达变化表明它们在动脉粥样硬化发生发展过程中起重要作用。     

脂代谢相关基因在低密度脂蛋白受体基因缺失幼龄小鼠肝脏中的表达分析

目的 探讨脂代谢相关基因在低密度脂蛋白受体(LDLR)基因缺失(LDLR-/-)小鼠肝脏中的表达特征及其与血脂紊乱和动脉粥样硬化早期病变的关系.方法 应用RT-PCR技术分析14、30、60和90天龄LDLR-/-与野生型(WT)小鼠靶基因表达差异,并进行血生化及主动脉形态学检测.结果 与同龄WT小鼠相比,LDLR-/-小鼠肝脏中载脂蛋白AⅣ、脂肪酸转运酶和肉碱棕榈酰转移酶Ⅰ的mRNA水平在14天龄时即显著下调(P＜0.05);30天龄时载脂蛋白A Ⅰ显著上调,载脂蛋白F则显著下调(P＜0.05);60天龄时肝X受体α显著升高(P＜0.05),酰基辅酶A氧化酶1在90天龄时显著下调(P＜0.05);载脂蛋白A Ⅴ、载脂蛋白E、过氧化物增殖物激活受体α和血管生成素样蛋白3差异无统计学意义(P＞0.05).血清总胆固醇、甘油三酯和低密度脂蛋白C含量从14天龄起均显著高于同龄WT小鼠(均P＜0.05),并随年龄增长持续升高.结论 上述脂代谢相关基因在幼龄小鼠即发生表达水平的改变,与血脂紊乱及主动脉病变发生过程呈正相关,说明其可能共同参与幼龄小鼠的脂质代谢紊乱,进而影响动脉内皮细胞功能改变乃至动脉粥样硬化早期病变的发生.     

Increased plasma levels of LDL cholesterol in rabbits after adenoviral overexpression of human scavenger receptor class B type I

Scavenger receptor class B type I (SR-BI), a CD36 family member, plays a key role in high-density lipoprotein (HDL) metabolism, reverse cholesterol transport, and whole body cholesterol homeostasis, and is shown to be involved in the development of atherosclerosis in mice. In this report, we describe the effects of the adenoviral overexpression of human SR-BI (hSR-BI) in New Zealand White (NZW) rabbits, a wild-type animal model that expresses cholesteryl ester transfer protein (CETP) in plasma, displays a manlike lipoprotein profile, and is susceptible to atherosclerosis. A total of 1×10¹² adenoviral particles containing either hSR-BI or lacZ complementary deoxyribonucleic acid (control) were infused into the ear vein of NZW rabbits. Transgene expression was ascertained by TaqMan Real Time polymerase chain reaction measurements. Rabbits infected with Ad/hSR-BI (adenoviral plasmids containing hSR-BI) showed a faster clearance of administered [³H]HDL cholesterol and significantly decreased apolipoprotein (apo) A-I levels when compared to control rabbits, respectively. Interestingly, we found markedly increased levels of low-density lipoprotein (LDL) cholesterol exclusively in SR-BI-overexpressing rabbits. These changes were not accompanied by alterations in LDL receptor expression but by increased levels of CE transfer in these animals. By lowering HDL cholesterol and increasing plasma apoB-containing lipoprotein levels, the overexpression of SR-BI leads to a lipoprotein pattern, which is believed to enhance the development of atherosclerosis. The role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits—a CETP-expressing animal model displaying a manlike lipoprotein profile—may therefore be different from the one found in rodents.     

Rosuvastatin reduces gliosis and the accelerated weight gain observed in WT and ApoE-/- mice exposed to a high cholesterol diet

The influence of a high cholesterol (HC) diet on brain pathology is being recognized increasingly and is of immense interest. Previous findings from our laboratory demonstrated that a high cholesterol diet increases gliosis, astrocytic reactivity and neuroinflammation in both wild type (WT) and apolipoprotein knockout (ApoE-/-) mice. In the present study, we analyzed whether this increase in astrocytic reactivity, monitored by the number of cells in the hippocampus labelled with glial fibrillary acidic protein (GFAP), could be reduced by the use of rosuvastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. Furthermore, we studied the effect of rosuvastatin on changes in lipoprotein levels and weight gain, and their correlation to gliosis, in mice fed a high cholesterol diet. A significant increase in weight, total-cholesterol (TC) and low-density lipoprotein (LDL) levels were observed in WT and ApoE-/- mice on a HC diet. The number of GFAP labelled cells was found to be significantly increased in mice on a HC diet and reduced in rosuvastatin-treated WT and ApoE-/- mice on a HC diet. A significant reduction of weight, total-cholesterol and LDL levels was observed in rosuvastatin-treated WTHC mice. Significant correlations were found between changes in body weight, GFAP labelled cells and plasma total-cholesterol levels in WT and ApoE-/- mice. However, the correlations were found to be weaker for the GFAP labelled cells in the ApoE-/- mice. The results indicate that the observed reduction of gliosis by rosuvastatin treatment may be due to mechanisms that are independent of its lipid-lowering effect.     

Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia

Typically, autosomal dominant familial hypercholesterolaemia (FH) is caused by mutations in the low density lipoprotein (LDL) receptor or apolipoprotein B genes that result in defective clearance of plasma LDL by the liver, but a third gene (PCSK9), encoding a putative proprotein convertase, has recently been implicated. Two independent microarray studies support a role for PCSK9 in sterol metabolism and adenoviral-mediated over-expression of PCSK9 in mouse liver depletes hepatic LDL-receptor protein, but the mechanism by which dominant mutations cause human FH is unclear. We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor. We have stably expressed wild-type (WT) and variant PCSK9 in McArdle-7777 rat hepatoma cells and shown by confocal microscopy that all forms of PCSK9 co-localize with protein disulphide isomerase in the ER whether or not they can be autocleaved. Expression of the proposed pathogenic variants, but not of WT, S386A or F216L PCSK9, increases secretion of apolipoprotein B100-containing lipoproteins from the cells by 2-4-fold probably by reducing the degradation of nascent protein; no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants. This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers.     

Effects of short-term melatonin administration on lipoprotein metabolism in normolipidemic postmenopausal women

OBJECTIVE: To investigate the effects of short-term administration of melatonin on lipoprotein metabolism in normolipidemic postmenopausal women. METHODS: Fifteen such women received 6.0 mg melatonin daily for 2 weeks. Blood was sampled before and after treatment. We measured concentrations of total cholesterol and total triglyceride in the plasma, as well as the levels of cholesterol, triglyceride, and protein in the very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Plasma apolipoprotein levels were determined by immunoturbidimetric assay. Activities of lipoprotein lipase, hepatic triglyceride lipase, and lecithin cholesterol acyltransferase were also determined by enzymatic analysis. RESULTS: Melatonin administration significantly increased the plasma levels of triglyceride by 27.2% (P < 0.05), of VLDL-cholesterol by 37.2% (P < 0.01), of VLDL-triglyceride by 62.2% (P < 0.001), and of VLDL-protein by 30.0% (P < 0.05). However, the plasma total cholesterol level and the concentration of lipid and protein in LDL and HDL were not significantly affected. Melatonin significantly increased the plasma levels of apolipoprotein C-II by 29.5% (P < 0.005), of C-III by 17.1% (P < 0.001), and of E by 7.6% (P < 0.05). The plasma levels of apolipoprotein A-I, A-II, and B were not altered. Melatonin significantly inhibited the activity of lipoprotein lipase by -14.1% (P < 0.05), but did not significantly affect the activities of hepatic triglyceride lipase or of lecithin cholesterol acyltransferase. CONCLUSIONS: Findings indicate that melatonin increases the plasma level of VLDL particles by inhibiting the activity of lipoprotein lipase, but may not affect the plasma levels of LDL and HDL particles in postmenopausal women with normolipidemia.     

Effects of high cholesterol diet on gliosis in apolipoprotein E knockout mice. Implications for Alzheimer's disease and stroke

Hypercholesterolemia has been suggested as a risk factor for Alzheimer's disease (AD). A genetic risk factor for AD is the E4 allele of apolipoprotein E (apoE). ApoE is the major lipoprotein transporter in the brain, and is mainly produced by glial cells. The present study is focussed on analysing the effects of high cholesterol (HC) diet, duration 9 months, on glial activation in the brain, both in wild type (WT) mice and in mice with a null mutation in the apoE gene (knock-out, KO) mice. The activation of astrocytes and microglia was analysed after immunohistochemical labelling of glial fibrillary acidic protein (GFAP), and F4/80, respectively. In addition, the expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) was analysed. There was a marked stimulation of astrocyte and microglial activation as well as induced expression of NQO1 in the hippocampus and cerebral cortex upon HC diet. Furthermore, there was significant astrocyte activation in the apoE KO mice, as compared to the WT mice, on ND. The long time exposure to HC diet combined with apoE deficiency resulted in a synergistic effect on the expression of NQO1 in the brain.     

Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein

Lipopolysaccharide (LPS), the major outer membrane component of gram-negative bacteria, is a potent endotoxin that triggers cytokine-mediated systemic inflammatory responses in the host. Plasma lipoproteins are capable of LPS sequestration, thereby attenuating the host response to infection, but ensuing dyslipidemia severely compromises this host defense mechanism. We have recently reported that Escherichia coli J5 and Re595 LPS chemotypes that contain relatively short O-antigen polysaccharide side chains are efficiently redistributed from high-density lipoproteins (HDL) to other lipoprotein subclasses in normal human whole blood (ex vivo). In this study, we examined the role of the acute-phase proteins LPS-binding protein (LBP) and phospholipid transfer protein (PLTP) in this process. By the use of isolated HDL containing fluorescent J5 LPS, the redistribution of endotoxin among the major lipoprotein subclasses in a model system was determined by gel permeation chromatography. The kinetics of LPS and lipid particle interactions were determined by using Biacore analysis. LBP and PLTP were found to transfer LPS from HDL predominantly to low-density lipoproteins (LDL), in a time- and dose-dependent manner, to induce remodeling of HDL into two subpopulations as a consequence of the LPS transfer and to enhance the steady-state association of LDL with HDL in a dose-dependent fashion. The presence of LPS on HDL further enhanced LBP-dependent interactions of LDL with HDL and increased the stability of the HDL-LDL complexes. We postulate that HDL remodeling induced by LBP- and PLTP-mediated LPS transfer may contribute to the plasma lipoprotein dyslipidemia characteristic of the acute-phase response to infection.