低密度脂蛋白受体基因敲除鼠极低密度脂蛋白和中间密度脂蛋白组分诱导J774巨噬细胞胆固醇酯蓄积

为探讨低密度脂蛋白受体基因敲除鼠血浆极低密度脂蛋白和中间密度脂蛋白组分致动脉粥样硬化的作用,采用密度梯度序列超速离心法从低密度脂蛋白受体基因敲除鼠血浆分离极低密度脂蛋白和中间密度脂蛋白组分,用日立７４５０ 自动分析仪测定其脂含量,琼脂糖凝胶电泳和聚丙烯酰胺凝胶电泳测定其电泳迁移率和载脂蛋白组成,并与鼠腹腔巨噬细胞共同孵育,观察它与巨噬细胞的相互作用。结果发现, 低密度脂蛋白受体基因敲除鼠血浆极低密度脂蛋白和中间密度脂蛋白组分与Ｊ７７４ 巨噬细胞孵育后,细胞胆固醇酯水平［（７３±０ ．５） μｍｏｌ（ｇ．ｃｅｌｌｐｒｏｔｅｉｎ）］ 非常显著地大于空白对照组（ Ｐ＜ ０．００５） , 是天然低密度脂蛋白诱导细胞胆固醇酯［（８±７） μｍｏｌ（ｇ．ｃｅｌｌｐｒｏｔｅｉｎ）］蓄积的９ 倍。结果提示,低密度脂蛋白受体缺失鼠血浆非修饰极低密度脂蛋白和中间密度脂蛋白组分可被Ｊ７７４ 巨噬细胞摄取,转巨噬细胞为泡沫细胞。     

氧化型脂蛋白(a)对鼠腹腔巨噬细胞增殖的影响

为探讨氧化型脂蛋白（ａ）对巨噬细胞增殖的影响,采用细胞计数和ＭＴＴ掺入观察比较天然型脂蛋白（ａ）、氧化型脂蛋白（ａ）和丙二醛修饰脂蛋白（ａ）对培养的鼠腹腔巨噬细胞增殖的影响。结果发现,氧化型脂蛋白（ａ）在蛋白浓度为２．５～４０ｍｇ／Ｌ时刺激巨噬细胞增殖,蛋白浓度为４０ｍｇ／Ｌ时巨噬细胞数为对照组的１．５倍（Ｐ〈０．０５）。而天然型脂蛋白（ａ）和丙二醛修饰脂蛋白（ａ）对巨噬细胞增殖无影响。结果提示,氧化型脂蛋白（ａ）可能通过促进巨噬细胞增殖加速动脉粥样硬化的发展。     

正常人两种极低密度脂蛋白亚组分对小鼠腹腔巨噬细胞脂质堆积的影响

本文研究了正常人极低密度脂蛋白（ｖｅｒｙｌｏｗｄｅｎｓｉｔｙｌｉｐｏｐｒｏｔｅｉｎ，ＶＬＤＬ）两种亚组分，即贫含载脂蛋白Ｅ的ＶＬＤＬ和富含载脂蛋白Ｅ的ＶＬＤＬ对小鼠腹腔巨噬细胞（ｍｏｕｓｅｐｅｒｉｔｏｎｅａｌｍａｃｒｏｐｈａｇｅ，ＭＰＭ）脂质堆积的影响。将贫含载脂蛋白Ｅ的ＶＬＤＬ和富含载脂蛋白Ｅ的ＶＬＤＬ分别与ＭＰＭ温育２４ｈ后，细胞内甘油三酯（ｔｒｉｇｌｙｃｅｒｉｄｅ，ＴＧ）和胆固醇酯（ｃｈｏｌｅｓｔｅｒｙｌｅｓｔｅｒ，ＣＥ）随ＶＬＤＬ浓度的增加而增加（方差分析，Ｐ＜０．０５），且对ＭＰＭ内ＴＧ的增加量以贫含载脂蛋白Ｅ的ＶＬＤＬ居多（Ｐ＜０．０１），而对ＭＰＭ内ＣＥ的增加量两者无显著性差异（Ｐ＞０．０５）。这提示，贫含载脂蛋白Ｅ的ＶＬＤＬ和富合载脂蛋白Ｅ的ＶＬＤＬ均能促进ＭＰＭ内ＴＧ、ＣＥ堆积，从而使巨噬细胞（ｍａｃｒｏｐｈａｇｅ，ＭＰ）转变为泡沫细胞。     

低密度脂蛋白免疫复合物对小鼠腹腔巨噬细胞胆固醇酯蓄积和一氧化氮释放的影响

目的 探讨低密度脂蛋白免疫复合物对小鼠腹腔巨噬细胞胆固醇酯的蓄积和一氧化氮释放的影响。方法 密度梯度超速离心从新鲜人血浆分离天然低密度脂蛋白，与抗低密度脂蛋白抗血清IgG组分制备低密度脂蛋白免疫复合物，低密度脂蛋白免疫复合物与小鼠腹腔巨噬细胞孵育后采用酶荧光法检测细胞胆固醇酯含量，进行细胞形态学观察和组织化学分析．并用硝酸还原酶法测定细胞释放至培养基中的一氧化氮量。结果 低密度脂蛋白免疫复合物剂量依赖性地诱导巨噬细胞内胆固醇酯的大量堆积，其效应显著强于氧化型低密度脂蛋白（P〈0．01）。经低密度脂蛋白免疫复合物处理的巨噬细胞呈典型泡沫细胞状，与猩红强染色，而天然低密度脂蛋白、抗低密度脂蛋白IgG处理的巨噬细胞内未见胆固醇酯的蓄积。此外，低密度脂蛋白免疫复合物剂量依赖性地抑制巨噬细胞一氧化氮的分泌。结论 低密度脂蛋白免疫复合物不仅通过致小鼠腹腔巨噬细胞泡沫化，也通过损伤巨噬细胞分泌一氧化氮的功能参与致动脉粥样硬化作用。     

亚硝酸盐对培养心肌细胞的直接作用

应用亚硝酸钠作用于培养的心肌细胞，观察到心肌细胞发生了超微形态结构改变；细胞内α－羟丁酸脱氢酶漏出增加（Ｐ＜０．０５～０．０１），３Ｈ—ＴｄＲ掺入变化呈双向性：小剂量组（０．００１～０．１×１０－６ｍｏｌ／Ｌ）呈现促进作用（Ｐ＜０．０５～０．０１）；大剂量组（１．０×１０－６ｍｏｌ／Ｌ）则表现为抑制效应（Ｐ＜０．０５）。细胞周期分析结果：小剂量组（０．０１×１０－６ｍｏｌ／Ｌ）Ｇ０Ｇ１期细胞减少４．１３％，Ｓ期增长３．９５％，Ｇ２＋Ｍ期增长０．３３％，与对照组比较，无显著性差异（Ｐ＞０．０５）。大剂量组（１、０×１０－６ｍｏｌ／Ｌ）Ｇ０Ｇ１期细胞增加９．１４％，Ｓ期减少１２．４６％，Ｇ２＋Ｍ期增加４．０６％，其中Ｓ期的改变达到显著差异（Ｐ＜０．０５）；细胞及培养液中脂质过氧化物含量增加（Ｐ＜０．０１）。表明亚硝酸盐能引起培养心肌细胞的直接损伤，其机理与脂质过氧化作用有关。     

3种肺泡巨噬细胞因子对慢性支气管炎发病的影响

目的为了解肺泡巨噬细胞（ＡＭ）释放的肿瘤坏死因子α（ＴＮＦα）、血栓素Ｂ２（ＴｘＢ２）、６酮－前列腺素Ｆ１α（６－ｋｅｔｏ－ＰＧＦ１α）在慢性支气炎发病中的作用。方法应用支气管肺泡灌洗（ＢＡＬ）技术采集１２例慢性支气管炎缓解期患者和１２例正常人的肺泡巨噬细胞，进行体外培养并测定上述３种细胞因子含量。结果慢支组ＡＭ合成分泌的３种细胞因子含量均较正常人组高（Ｐ＜０．０５）；随着培养液中ＬＰＳ浓度的增加，两组ＡＭ合成分泌的３种细胞因子含量均逐渐增加，两组间存在显著差异性（Ｐ＜０．０５）。结论慢支缓解期患者ＡＭ更易活化释放这些炎性介质，对慢支发生发展有重要影响。     

血脂康和辛伐他汀对高胆固醇血症调脂作用的比较

目的研究血脂康对高胆固醇血症患者的调脂作用并与辛伐他汀比较。方法２８例高胆固醇血症患者随机分为两组，服药前及服药后４、８周测定血脂。结果（１）服药后４周ＴＣ分别降低了２０７％和２２５％（Ｐ值均＜０００１）；血脂康降低血清低密度脂蛋白胆固醇（ＬＤＬＣ）作用与辛伐他汀相似，ＬＤＬＣ水平分别降低了２８２％和３３％（Ｐ值均＜００１）；（２）血脂康明显降低１７４％的血清ＴＧ水平（Ｐ＜００５）；（３）服血脂康和辛伐他汀４周后，载脂蛋白（Ａｐｏ）Ａ１却分别增加了１２７％和１３６％（Ｐ值均＜００１）；ＡｐｏＢ水平均下降了８％左右（Ｐ＜００５）；分别使脂蛋白（ａ）［Ｌｐ（ａ）］水平降低了３１３％（Ｐ＜００１）和２７８％（Ｐ＜００５）；（４）除了治疗８周后Ｌｐ（ａ）水平进一步下降外，两种药物治疗８周后的调脂作用与４周比较无明显差异。结论血脂康能显著降低Ⅱａ和Ⅱｂ型高胆固醇血症患者血清ＴＣ和ＬＤＬＣ，其作用与辛伐他汀相等；血脂康降低ＴＧ作用优于辛伐他汀     

戊酸雌二醇对18月龄雌性大鼠下丘脑内阿片肽基因表达的调节作用

目的观察戊酸雌二醇对１８月龄雌性老年前期大鼠下丘脑、垂体和血浆内阿片肽含量及下丘脑内阿片肽ｍＲＮＡ水平的影响。方法采用ＮｏｒｔｈｅｒｎＢｌｏｔ和神经肽放免测定法。结果与５月龄青年大鼠比较，１８月龄大鼠下丘脑和血浆β－内啡肽（β－ＥＰ）、亮氨酸脑啡肽（Ｌ－ＥＮＫ）、强啡肽Ａ１－１３（ＤｙｎＡ１－１３）含量明显降低（Ｐ＜０．０５或０．０１）；垂体β－ＥＰ、Ｌ－ＥＮＫ含量升高，ＤｙｎＡ１－１３含量降低（Ｐ＜０．０１）；下丘脑阿黑皮素原（ＰＯＭＣ）基因和脑啡肽原（ｐｒｏｅｎｋｅｐｈａｌｉｎ）基因ｍＲＮＡ水平明显低于青年大鼠（Ｐ＜０．０５）。肌注戊酸雌二醇后，老年前期大鼠下丘脑ＰＯＭＣ和ｐｒｏｅｎｋｅｐｈａｌｉｎ基因ｍＲＮＡ水平明显升高（Ｐ＜０．０５）；下丘脑β－ＥＰ含量增加（Ｐ＜０．０５）；垂体β－ＥＰ降低，Ｌ－ＥＮＫ升高；血浆ＤｙｎＡ１－１３含量增加（Ｐ＜０．０５）。结论戊酸雌二醇促进老年前期雌性大鼠下丘脑β－ＥＰ基因表达，增强其合成能力，而对Ｌ－ＥＮＫ和ＤｙｎＡ代谢的影响不明显。     

性激素对阉割雄鼠免疫力和生存能力的影响

切除性腺雄鼠定期接受雌或雄性激素治疗，在１～１８月龄段，经雌二醇治疗的雄鼠平均死亡月龄高于安慰剂组３８％（Ｐ＜０．０１），高于雄激素治疗组６３％（Ｐ＜０．０５）；在１～２１月龄段，经雌二醇和孕酮联合治疗的动物死亡月龄高于雄激素治疗组４６％（Ｐ＜０．０５）。免疫学研究发现，雌二醇可明显提高雄鼠淋巴细胞转化能力（Ｐ＜０．０１）以及腹腔巨噬细胞吞噬能力（Ｐ＜０．００１）。生化研究表明，雌性激素可明显降低雄鼠血中胆固醇含量（Ｐ＜０．０５～０．００５）。结果提示，雌性激素对于延缓衰老具有深远的意义。     

肝硬化患者胃,十二指肠粘膜六种胃肠激素含量变化及其临床意义

本文研究了肝硬化（ＨＣ）患者胃、十二指肠粘膜６种胃肠激素含量变化及其意义。结果表明，肝硬化患者胃粘膜血管活性肠肽（ＶＩＰ）含量明显增加（Ｐ＜０．０５）；胃动素明显降低（Ｐ＜０．０１）。十二指肠（Ｄ）、粘膜生长抑素（ＳＳ）、脑啡肽含量明显减少（Ｐ＜０．００５）；血管加压素β－内啡肽（β－ＥＰ）明显增加（Ｐ＜０．０５）、ＶＩＰ含量与胃、Ｄ粘膜充血程度呈正相关（Ｐ＜０５），与有、无腹水及其程度关系不密切（Ｐ＞０．１），与食道静脉曲张程度有一定联系，但不显著（Ｐ＝０．１）。胃粘膜β－ＥＰ、Ｄ粘膜ＳＳ含量随肝功能下降而递增（Ｐ＜０．０５）。提示ＨＣ患者充血性胃肠粘膜病变及消化不良等可能与粘膜胃肠激素含量异常有关。     

Marine lipids normalize cholesteryl ester transfer in IDDM

Summary Patients with insulin-dependent diabetes mellitus (IDDM) have a pathological increase in cholesteryl ester transfer (CET) that enriches the apolipoprotein B-containing lipoproteins with cholesteryl ester and increases their atherogenicity. Since we have shown earlier that omega-3 (n-3) fatty acids present in marine lipids normalize both CET and lipoprotein composition in non-diabetic patients with hypercholesterolaemia, we sought to determine whether the same beneficial effects could be achieved in nine normolipidaemic (triglycerides 1.10; cholesterol 4.94, high density lipoprotein 1.10 mmol/l) IDDM patients (fructosamine 424±156; normal 174–286 mol/l) treated for 2 months with n-3 fatty acids (4.6 g/day). Before treatment, CET measured by both mass and isotopic assays was abnormally accelerated (p<0.001). While marine lipids modestly decreased triglyceride levels (–14%; p<0.05), CET fell dramatically in all subjects (mass assay: –97% at 1 h; isotopic assay: –58%; p<0.001) to below control levels with no change in glycaemic control (fructosamine 408±103 mol/l). The mass of cholesteryl ester transfer protein paradoxically increased significantly (pre-treatment: 2.04±0.86 vs post-treatment 2.48±0.97 g/ml; p<0.05). Since it is believed that accelerated CET promotes the formation of atherogenic cholesteryl ester-enriched apo B-containing lipoproteins, the capacity of marine lipids to reverse this functional abnormality without altering glycaemic control suggests that these agents may have an adjunctive role to play in the nutritional therapy of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - CET cholesteryl ester transfer - CETP cholesteryl ester transfer protein - HDL high density lipoprotein - LpL lipoprotein lipase - apo B apolipoprotein B - n-3 fatty acids omega-3 fatty acids     

Plasma lipoproteins from patients with poorly controlled diabetes mellitus and “in vitro” glycation of lipoproteins enhance the transfer rate of cholesteryl ester from HDL to apo-B-containing lipoproteins

Summary Alterations in the reverse cholesterol transport system have been described in diabetic mellitus patients in several but not all studies. Furthermore, recently published investigations suggest that a faster “in vitro” transfer rate of cholesteryl ester from high density lipoproteins to apoB-containing lipoproteins could be solely ascribed to variation of the plasma lipoprotein composition and concentration in the diabetic state. The present study analysed the influence of lipoprotein glycation on the cholesteryl ester transfer protein-mediated transfer of esterified cholesterol from high density lipoprotein and its subfractions to lighter density lipoproteins. For this purpose two sets of “in vitro” experiments were carried out utilizing:1) plasma lipoproteins drawn from diabetic and from normal subjects and; 2) normal lipoproteins or partially purified cholesteryl ester transfer protein submitted to “in vitro” glycation. The transfer rate of ¹⁴C-cholesteryl ester labelled HDL subfractions to low or very low density lipoproteins was measured in all experiments. After incubations with plasma d > 1.21 g/ml or with purified cholesteryl ester transfer protein, apoB-containing lipoproteins were precipitated with a dextran sulfate/MgCl₂ solution. The “in vitro” glycation of the partially purified cholesteryl ester transfer protein markedly impaired its activity. However, greater transfer rates were observed when lipoproteins from diabetic individuals or the “in vitro” glycated lipoproteins were utilized. This effect was attributed to glycation of the protein component of HDL. In conclusion, lipoprotein glycation elicits an enrichment of the apoB-containing lipoproteins with cholesteryl ester that is likely related to the premature atherosclerosis in patients with poorly controlled diabetes. [Diabetologia (1997) 40: 1085–1093] Received: 14 January 1997 and in revised form: 7 May 1997     

Lipoprotein profile and cholesteryl ester transfer protein in neonates

Undernourishment in utero appears to be associated with persisting changes in the metabolic, endocrine, and immune functions. In this study, we determined the influence of birth weight on the lipoprotein profile and cholesteryl ester transfer protein (CETP), which promotes a proatherogenic lipoprotein profile in plasma by determining the chemical, physical, and biologic properties of the respective lipoprotein particles. Triglyceride (TG) concentrations were highest and high-density lipoprotein (HDL)(2)-cholesterol levels were lowest in small for gestational age (SGA) neonates. CETP-mass was determined by enzyme-linked immunosorbent assay (ELISA) and CETP-activity by using exogenous lipoproteins. Cholesteryl ester transfer was determined as transfer of radiolabeled cholesteryl esters (CE) from HDL to apolipoprotein B-containing lipoproteins. CETP mass was lowest and cholesteryl ester transfer was highest in SGA neonates. CETP-activity did not differ among the neonates. Our results suggest that increased and decreased nourishment in utero affects the lipoprotein profile and CETP in neonates. High TG and low HDL(2) levels in SGA neonates might result from increased cholesteryl ester transfer and, may in part, explain the increased risk of coronary heart disease (CHD) of small for gestational age neonates in later life.     

Inhibiting low-density lipoprotein glycation ameliorates increased cholesteryl ester synthesis in macrophages and hypercholesterolemia and aortic lipid peroxidation in streptozotocin diabetic rats

Increased nonenzymatic glycation of apolipoprotein (apo) B-containing lipoproteins impairs uptake and metabolism by the high-affinity low-density lipoprotein receptor and is one of the postsecretory modifications contributory to accelerated atherosclerosis in diabetes. The present study evaluated in vitro and in vivo effects of 2,2-chlorophenylaminophenylacetate to probe the influence of glycated lipoprotein on cholesterol homeostasis. This compound prevented the increased formation of glycated products in low-density lipoprotein incubated with 200 mmol/L glucose and the increased cholesteryl ester synthesis in THP-1 macrophages induced by apo B-containing lipoproteins preincubated with high glucose concentration. The elevated circulating concentrations of glycated lipoprotein and cholesterol and higher vascular levels of lipid peroxidation products observed in streptozotocin diabetic rats compared with nondiabetic controls were significantly reduced in diabetic animals treated for 6 months with test compound. These results are the first to demonstrate that inhibiting nonenzymatic glycation of apo B-containing lipoproteins ameliorates abnormalities contributory to hypercholesterolemia and atherogenic risk in diabetes.     

Serum lipids and apolipoproteins in children with Type 1 (insulin-dependent) diabetes during the first two years of the disease

Summary Serum lipoproteins and apolipoproteins were studied at diagnosis and 6,12 and 24 months later in 30 consecutive children aged 3–15 years with newly detected Type 1 (insulin-dependent) diabetes mellitus (December 1982–October 1984) and in 44 healthy control children. Serum triglycerides at diagnosis were significantly higher than after 6–24 months and also higher than in the control group (p<0.001). At follow-up, triglycerides in the very low density lipoproteins and low density lipoproteins were restored to normal, while high density lipoprotein triglycerides remained high. Serum cholesterol at onset of diabetes was significantly higher than in the control children (p<0.01), mainly because of increased very low density lipoprotein cholesterol (p<0.001). Cholesterol in serum and in the serum lipoprotein fractions was similar to that in the control children at follow-up, except that high density lipoprotein cholesterol was higher in the diabetic children after 6 months. The concentrations of the serum apolipoproteins A-I, A-II and B were higher at onset of diabetes than in the control children (p<0.001, p<0.01, p<0.05 respectively), with a significantly increased ratio of apolipoprotein A-I to A-II in the diabetic children (p<0.001). The serum apolipoprotein concentrations were normalised during treatment. The ratio of apolipoprotein A-I to B did not differ from that in control children. On admission, there were strong positive correlations between HbA_1c and the concentrations of the very low density lipoproteins and the low density and high density lipoprotein triglycerides. There were also significantly positive correlations (p<0.01) between HbA_1c and apolipoprotein A-I and apolipoprotein B respectively. After treatment these correlations disappeared, except for a positive correlation with very low density lipoprotein triglycerides at 2 years. In conclusion, at diagnosis, when the diabetic children were in an insulin-deficient state, all apolipoproteins and serum lipoprotein fractions, except cholesterol in high density lipoproteins and low density lipoproteins were increased. During the first two years of treatment the concentrations of lipoproteins and apolipoproteins in serum are similar to those in healthy children.     

消斑肽能逆转平滑肌细胞源性泡沫细胞

培养的猪主动脉平滑肌细胞，在与１０ｍｇ·Ｌ－１氧化型低密度脂蛋白作用７２ｈ后，细胞内蓄积胆固醇酯，使胆固醇酯占总胆固醇的６４．１％，形成泡沫细胞。然后向泡沫细胞的培养基中加入不同浓度的消斑肽，作用２４ｈ后，发现总胆固醇和胆固醇酯均下降，而且胆固醇酯小于总胆固醇的５０％，提示泡沫细胞发生了逆转。在平滑肌细胞源性泡沫细胞的形成过程中，一氧化氮合成增加，与对照组的差别有显著性，而在逆转过程中一氧化氨合成下降，与对照组差别无显著性，提示消斑肽有使一氧化氮合成功能恢复正常的作用。     

Scavenger receptor type BI potentiates reverse cholesterol transport system by removing cholesterol ester from HDL

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system.     

Inhibition of Akt phosphorylation by thrombin,histamine and lysophosphatidylcholine in endothelial cells. Differential role of protein kinase C

This randomised, double-blind, placebo-controlled crossover study evaluated the effects of rosuvastatin (40 mg/day for 8 weeks) on atherogenic apolipoprotein B-containing lipoprotein subfractions. Subjects, recruited based on raised plasma triglyceride (TG) or low-density lipoprotein cholesterol (LDL-C), were divided into normotriglyceridaemic (NTG, n = 13; TG < 2.0 mmol/l) and hypertriglyceridaemic (HTG, n = 16; TG > or = 2.0 mmol/l) groups. Similar reductions on rosuvastatin were observed for both groups in LDL-C (NTG -60%; HTG -56%), apoB (both -49%), intermediate-density lipoprotein (NTG -57%; HTG -54%) and LDL circulating mass (NTG -52%, HTG -58%) (all P < 0.001 versus placebo), i.e., these changes were phenotype independent. Phenotype dependency in response was observed in HTG relative to NTG in concentration of small dense LDL (LDL-III) (NTG -44%, P = NS; HTG -69%, P < 0.001), very-low-density lipoprotein1 (NTG -18%, P = NS; HTG 46%, P < 0.01), and remnant-like particle cholesterol (NTG -31%, P = NS; HTG -48%, P < 0.05). Rosuvastatin reduced cholesteryl ester transfer protein (CETP) by 33% in NTG and 37% in HTG (both P < 0.001); a reduction in cholesteryl ester transfer activity (-59%, P < 0.001) was observed in HTG only. Rosuvastatin therefore, in addition to lowering LDL and apoB-concentrations, largely corrected the TG and LDL abnormalities in subjects who had the propensity to develop the atherogenic lipoprotein phenotype.     

Cholesteryl Ester Transfer Protein Inhibition in Cardiovascular Risk Management: Ongoing Trials will End the Confusion

As delineated in this review, cholesteryl ester transfer protein (CETP) contributes to an atherogenic lipoprotein profile by redistributing cholesteryl esters from high density lipoprotein (HDL) toward apolipoprotein B‐containing lipoproteins, especially when the concentration of acceptor triglyceride‐rich lipoproteins is elevated. However, this lipid transfer protein may have antiatherogenic proprerties as well. Experimental evidence is accumulating which suggests that the atheroprotective reverse cholesterol transport pathway, whereby cholesterol is removed from peripheral macrophages to the liver for metabolism and biliary excretion, is stimulated by CETP in vivo. CETP could also play a role in host defense against infection and inflammatory processes. Moreover, recently published observational studies show that higher CETP levels may confer cardiovascular protection, whereas reported associations of cardiovascular disease (CVD) with CETP gene variations are equivocal. The concept that HDL cholesterol raising through inhibition of CETP may ameliorate CVD risk has been challenged by the failure of the CETP inhibitor, torcetrapib. Adverse clinical outcome associated with the use of this CETP inhibitor has been attributed to off‐target effects, which relate to stimulation of aldosterone. Other CETP inhibitors, such as dalcetrapib and anacetrapib, are unlikely to increase blood pressure. Dalcetrapib is less potent than anacetrapib, which doubles HDL cholesterol. Both inhibitors considerably lower LDL cholesterol.Serious concerns remain about the validity of the concept that HDL cholesterol raising by means of CETP inhibition is a viable strategy. Results of ongoing clinical trials with these drugs will have to be awaited before making up the balance between possible benefits and harms related to pharmacological CETP inhibition.     

Alterations in serum lipids and apolipoproteins in male Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary The relationships between serum lipid, apolipoprotein levels and urinary albumin excretion were investigated in 20 male Type 1 (insulin-dependent) diabetic patients with microalbuminuria (overnight urinary albumin excretion between 10 and 200 g/min), in 18 male Type 1 diabetic patients without microalbuminuria and in 18 male control subjects. In the microalbuminuric patients low density lipoprotein cholesterol was higher than in the control subjects (p<0.05); the high density lipoprotein/low density lipoprotein cholesterol ratio was lower than in the normoalbuminuric diabetic patients (p<0.05), and in the control subjects (p<0.01); apolipoprotein B was higher than in the normoalbuminuric patients (p<0.05); the apolipoprotein A₁/B ratio was lower than in the normoalbuminuric diabetic patients (p<0.05). Serum triglyceride was higher in the microalbuminuric diabetic patients and in the control subjects than in the normoalbuminuric diabetic patients (p<0.05, for both), but was not different between the microalbuminuric diabetic patients and the control subjects. No significant differences between the 3 groups were present with respect to serum cholesterol, high density lipoprotein cholesterol and apolipoprotein A₁. In the 2 combined Type 1 diabetic groups there were significant correlations between urinary albumin excretion and the high density lipoprotein/low density lipoprotein cholesterol ratio (R -0.40, p<0.02), apolipoprotein B (R0.35, p<0.05) and the apolipoprotein A₁/B ratio (R -0.44, p<0.01). These results indicate microalbuminuria related differences in lipid and apolipoprotein levels in male Type 1 diabetic patients, which may contribute to an increased risk of cardiovascular disease.