空腹甘油三酯正常的2型糖尿病患者餐后血脂的动态变化

目的探讨空腹甘油三酯正常的2型糖尿病患者脂肪餐后血脂水平的动态变化。方法通过脂肪餐负荷试验对25例空腹甘油三酯正常的2型糖尿病患者和20例健康对照者进行餐后血脂代谢的研究。分别于餐前、餐后2、4、6和8h用酶法测定总胆固醇和甘油三酯,一步法测定高低密度脂蛋白,葡萄糖氧化酶法测定血糖,化学发光免疫分析法测定免疫反应胰岛素,计算曲线下甘油三酯面积和增加面积。结果两组餐后甘油三酯平均值都有所升高,峰值在餐后4h。但糖尿病组餐后8h甘油三酯仍明显高于空腹水平(P<0.05),而对照组在餐后8h甘油三酯已恢复接近空腹水平(P>0.05)。两组的高密度脂蛋白在餐后4h都有一个轻微的低谷出现,但无组间差异(P>0.05)。总胆固醇和低密度脂蛋白在餐后无明显变化。两组曲线下甘油三酯面积和增加面积与餐后4h血清甘油三酯水平的相关性最显著(P<0.05)。结论2型糖尿病患者餐后脂代谢异常发生在空腹血脂异常之前。有必要联合检测空腹与餐后4h的甘油三酯水平来全面反映甘油三酯代谢是否存在异常。     

Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits

Consumption of a range of dietary antioxidants may be beneficial in protecting low density lipoprotein (LDL) against oxidative modification, as studies have demonstrated that antioxidants other than vitamin E may also function against oxidation of LDL in vitro. In the present study, the effect of polyphenol antioxidants on the susceptibility of LDL to copper-mediated oxidation was investigated after feeding semi-purified diets to 3 groups of New Zealand white (NZW) rabbits. All diets comprised 40% energy as fat with 17% energy as oleic acid. Dietary fatty acid compositions were identical. Oils with different polyphenol contents were used to provide the dietary source of oleic acid — refined olive oil, extra virgin olive oil and Trisun high oleic sunflower seed oil. Polyphenolic compounds (hydroxytyrosol and p-tyrosol) could only be detected in the extra virgin olive oil. Vitamin E was equalised in all diets. LDL oxidizability in vitro was determined by continuously monitoring the copper-induced formation of conjugated dienes after 6 weeks of experimental diet feeding. The lag phase before demonstrable oxidation occurred was significantly increased in the high polyphenol, extra virgin olive oil group (P < 0.05) when compared with combined results from the low polyphenol group (refined olive oil and Trisun), even though the LDL vitamin E concentration in the high polyphenol group was significantly lower. The rate of conjugated diene formation was not influenced by the presence of dietary polyphenols. Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.     

The heparin-bound fraction of human lipoprotein-deficient serum inhibits endocytic uptake of oxidized low density lipoprotein by macrophages

We recently demonstrated that bovine lactoferrin, a cationic whey protein from bovine milk, interacts with the negative charges of modified low density lipoproteins (modified LDL) such as acetylated LDL (acLDL) and oxidized LDL (oxLDL), which markedly interferes with their endocytic uptake by rat peritoneal macrophages (Kajikawa M, Ohta T, Takase M, Kawase K, Shimamura S, Matsuda I. Biochim Biophys Acta 1994;1213:82–90). In the present study, we examined whether human lipoprotein-deficient serum (LPDS) might contain protein(s) that could inhibit the endocytic uptake of oxLDL by mouse macrophages. We fractionated LPDS by heparin affinity chromatography and found that the cellular binding of oxLDL to mouse macrophages and subsequent endocytic uptake were inhibited by 50%–60% with the heparin-bound fraction, whereas the heparin-unbound fraction had no effect. Similar results were obtained in the experiments with acetylated LDL. Sephacryl S-300 gel-filtration chromatography of a mixture of oxLDL and the heparin-bound fraction revealed that a 150-kDa protein was associated with oxLDL. These results indicate that the electrostatic interaction of oxLDL with some component(s) of the heparin-bound fraction might interfere with the endocytic uptake of oxLDL by the macrophage scavenger receptor.     

新疆哈萨克族人弗林蛋白Furin基因变异与高总胆固醇血症、高低密度脂蛋白胆固醇血症的相关性

目的 研究新疆哈萨克族人高总胆固醇血症、高低密度脂蛋白胆固醇血症与弗林蛋白(Furin)基因变异的相关性。方法 本研究是以横断面流行病学调查为基础的病例-对照研究,878例研究对象均来自新疆哈萨克族自然人群。测定48例随机选择的哈萨克族高胆固醇血症患者(女性24例、男性24例)弗林蛋白基因启动子、外显子区序列,筛查代表性变异。采用TaqMan PCR分析弗林蛋白基因变异在878例哈萨克族自然人群(男性370例、女性508例)中的分型,分析其与哈萨克族人血总胆固醇、低密度脂蛋白胆固醇水平的相关性。结果 在48例高胆固醇血症患者中,共筛查出弗林蛋白基因的12个变异,包括4个代表性变异(rs6226、rs6227、rs2071410、rs4932178)。4个代表性变异均在大样本哈萨克族人中基因型分型成功(成功率≥99%)。在哈萨克族自然人群中,rs6226、rs6227、rs2071410、rs4932178多态性的基因型、等位基因、单体型频率分别在高胆固醇血症组、对照组间及高低密度脂蛋白胆固醇血症组、对照组间的分布差异均无统计学意义(P均＞0.05);每个多态性的不同基因型携带者之间的血总胆固醇、低密度脂蛋白胆固醇平均水平差异无统计学意义(P均＞0.05)。结论 新疆哈萨克族人高总胆固醇血症、高低密度脂蛋白胆固醇血症与弗林蛋白基因变异不相关,该变异可能不是哈萨克族人高胆固醇血症、高低密度脂蛋白胆固醇血症的易感因素。     

载脂蛋白嵌合模拟肽通过NF-κB途径抑制ox-LDL诱导的巨噬细胞炎症反应

目的：探讨载脂蛋白嵌合模拟肽Ac-hE-18A-NH2对氧化型低密度脂蛋白(oxidized LDL,ox-LDL)刺激下巨噬细
胞肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)表达的影响及其作用机制。方法：Ox-LDL刺激RAW264.7巨噬细胞,
给予不同浓度的模拟肽Ac-hE-18A-NH2(1~100 μg/mL)干预,收集细胞,测定巨噬细胞TNF-α的分泌和mRNA表达水平。
Western印迹检测ATP结合盒转运蛋白A1(ATP-binding cassette transporter A1,ABCA1)及P-IκB蛋白浓度。EMSA检测核因
子-κB(nuclear factor-κB,NF-κB)活性。结果：Ox-LDL刺激使RAW264.7巨噬细胞TNF-α 分泌和mRNA表达明显增强,细
胞内胆固醇蓄积,促进IκB磷酸化,并激活NF-κB。Ac-hE-18A-NH2浓度依赖性地降低TNF-α 分泌及mRNA表达,上调
ABCA1 mRNA和蛋白的表达,减少细胞内胆固醇含量,抑制NF-κB活化,并抑制IκB磷酸化。相同的实验条件下及作
用浓度,D-4F对于TNF-α 分泌的抑制作用不如Ac-hE-18A-NH2。结论：Ac-hE-18A-NH2能抑制ox-LDL诱导的RAW264.7
巨噬细胞TNF-α分泌和mRNA表达,IκB/NF-κB-TNF-α信号通路是其中作用途径之一。Ac-hE-18A-NH2的抗炎作用优于
apoA-I模拟肽D-4F。     

LRP5基因多态性与绝经后妇女2型糖尿病伴骨质疏松症的相关性研究

目的探讨上海地区绝经后2型糖尿病和骨质疏松症妇女的低密度脂蛋白受体相关蛋白5基因多态性与骨密度、骨代谢、糖代谢的关系。方法选取上海市普陀区无亲缘关系的绝经后汉族妇女354例,其中骨质疏松组（A组）90例、2型糖尿病组（B组）96例、2型糖尿病伴骨质疏松组（C组）90例、健康老年对照组（D组）78例。运用双能X线骨密度仪检测腰椎（L2-4）及股骨颈骨密度,同时检测骨代谢指标：BALP、TRACP-5b;糖代谢指标：Hb A1c、FINS。应用基因测序技术检测LRP5基因A1330V位点多态性。采用协方差分析校正年龄、绝经年限、体重指数后比较LRP5基因多态性与骨密度的相关性。结果 A组LRP5基因A1330V位点CC型与CT/TT型相比腰椎骨密度增高（P〈0.05）,经年龄、绝经年限、BMI校正后仍有显著差异（P〈0.01）;D组LRP5基因A1330V位点多态性与HbA1c相关（P〈0.05）,CC型较CT/TT型HbA1c高,经年龄、绝经年限、BMI校正后无统计学意义（P〉0.05）。结论上海地区汉族绝经后骨质疏松症妇女LRP5基因型与腰椎骨密度相关,提示LRP5基因可能是上海地区汉族绝经后骨质疏松症妇女的易感基因。2型糖尿病患者BMD增高,可能与BMI、胰岛素水平增高有关。LRP5基因可能不是上海地区绝经后2型糖尿病妇女的易感基因。     

Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion

Apolipoprotein B （apoB） is the main protein component of very low density lipoprotein （VLDL） and is necessary for the assembly and secretion of these triglyceride （TG）-rich particles. Following release from the liver, VLDL is converted to low density lipoprotein （LDL） in the plasma and increased production of VLDL can therefore play a detrimental role in cardiovascular disease. Increasing evidence has helped to establish VLDL assembly as a target for the treatment of dyslipidemias. Multiple factors are involved in the folding of the apoB protein and the formation of a secretion-competent VLDL particle. Failed VLDL assembly can initiate quality control mechanisms in the hepatocyte that target apoB for degradation. ApoB is a substrate for endoplasmic reticulum associated degradation （ERAD） by the ubiquitin proteasome system and for autophagy. Efficient targeting and disposal of apoB is a regu- lated process that modulates VLDL secretion and partitioning of TG. Emerging evidence suggests that significant overlap exists between these degradative pathways. For example, the insulin-mediated targeting of apoB to autop- hagy and postprandial activation of the unfolded protein response （UPR） may employ the same cellular machinery and regulatory cues. Changes in the quality control mechanisms for apoB impact hepatic physiology and pathology states, including insulin resistance and fatty liver. Insulin signaling, lipid metabolism and the hepatic UPR may impact VLDL production, particularly during the postprandial state. In this review we summarize our current understanding of VLDL assembly, apoB degradation, quality control mechanisms and the role of these processes in liver physiology and in pathologic states.     

脑梗死患者血清同型半胱氨酸与小而密低密度脂蛋白胆固醇的关系

目的探讨血清同型半胱氨酸(Hcy)水平升高和小而密低密度脂蛋白胆固醇(sdLDL-C)水平在脑梗死发病中的作用。方法采用全自动生化分析仪检测124例脑梗死患者血清Hcy和sdLDL-C水平,同时检测血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、血糖水平。根据头颅CT和磁共振检查证实后将患者分为多发性脑梗死组与单发性脑梗死组,观察其与Hcy及sdLDL-C的关系。结果脑梗死组血清Hcy及血脂水平明显高于对照组(HDL-C低于对照组),P<0.05,Hcy与sdLDL-C水平随脑梗死病变程度增加而升高(P<0.05)。Hcy和sdLDL-C与脑梗死病变程度密切相关(r=0.259和r=0.452,P<0.001)。结论 Hcy和sdLDL-C均是脑梗死发病的独立危险因素。     

Genetic variants of apolipoprotein A5 T-1131C and apolipoprotein E common polymorphisms and their relationship to features of metabolic syndrome in adult dyslipidemic patients

Objectives

The aim was to evaluate the relationships of the T-1131C (rs662799) polymorphism variants of apolipoprotein A5 (Apo A5) gene and variants of apolipoprotein E (Apo E) gene common polymorphism (rs429358, rs7412) to signs of metabolic syndrome (MetS).

Design and methods

We examined 590 asymptomatic dyslipidemic patients divided into MetS + (n = 146) and MetS − (n = 444) groups according to criteria of NCEP ATPIII Panel. We evaluated genotype frequencies and differences in MetS features between individual groups. Logistic regression analysis was used for the evaluation of Apo A5/Apo E variants as possible risk factors for MetS.

Results

We found no statistical differences between genotype and allele frequencies for both Apo A5 and Apo E polymorphisms between MetS + and MetS − groups. In all subjects and MetS − group, we confirmed well-known association of the − 1131C Apo A5 minor allele with elevated triglycerides (TG, p < 0.001). The Apo E gene E2 and E4 variants were associated with higher levels of TG (p < 0.01) in comparison to E33 common variant. However, no statistical differences were observed in MetS + subjects, regardless of significantly higher TG levels in this group. Apo A5/Apo E variant analysis in all dyslipidemic patients revealed significant increase of TG levels in all subgroups in comparison to common − 1131T/E3 variant carriers, the most in − 1131C/E4 variant subgroup. Logistic regression analysis models showed no association of Apo A5, Apo E and all Apo A5/Apo E variants with metabolic syndrome, even after adjustment for age and sex.

Conclusion

Our study refined the role of Apo A5 and Apo E genetic variants in the group of adult dyslipidemic patients. We demonstrate that except of TG, Apo A5 T-1131C (rs662799) and Apo E (rs429358, rs7412) polymorphisms have no remarkable effect on MetS characteristics.     

Serum paraoxonase-1 activity is more closely related to HDL particle concentration and large HDL particles than to HDL cholesterol in Type 2 diabetic and non-diabetic subjects

Objectives

We determined relationships of the anti-oxidative enzyme, paraoxonase-1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM).

Design and methods

Serum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects.

Results

PON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p < 0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p < 0.05). PON-1 was more closely related to HDL cholesterol than to apoA-I (p = 0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p < 0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics.

Conclusions

PON-1 activity is more closely related to the HDL particle concentration or large HDL particles than to HDL cholesterol. Impaired PON-1 activity in T2DM is not to a considerable extent explained by altered HDL subfraction levels.