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第九届全国免疫学学术大会

作者： Ying Zhao Jun Wang Laura Calpe-Berdiel Amanda C.Foks Bart Lammers Johan Kuiper Theo J.C.Van Berkel Miranda Van Eck Department of Pathology and Pathophysiology Soochow University Division of Biopharmaceutics Leiden/Amsterdam Center for Drug ResearchLeiden University Institute of Biology and Medical Sciences Soochow University

Background:ldl receptor(ldlr)and ABC-transporter A1(ABCA1)are two distinct players in cellular cholesterol *** recognizes apoprotein B100 and apoE in lipoproteins to mediate the uptake of cholesterol,while ABCA1 promotes excess cholesterol efttux to apoprotein ***:The present study aims to investigate whether ldlr deficiency influences the atheroprotective effects of leukocyte ABCA1 in *** and Results:ldlr-/-mice were transplanted with bone marrow from ldlr/ABCA1mice,ldlr/ABCA1/-mice,and their respective *** leukocyte ABCA1 deficiency reduced plasma cholesterol levels,after 8weeks of Western-type diet feeding,animals transplanted with ldlr/ABCA1and ldlr/ABCA1bone marrow developed 1.6-fold(pldlr reduced lesion development(pldlr deficiency did not affect monocytosis,recruitment of moncocytes and macrophage foam cell ***,the deletion of leukocyte ABCA1 did reduce lymphocytosis and recruitment of T cells into the adventitia of lesions,associated with smaller lesion size in ldlr/ABCA1transplanted mice,indicating the potential contribution of lymphocytosis and recruitment ofT cells to ***:Leukocyte ldlr deficiency does not affect the atheroprotective effects of leukocyte ***,suppression of lymphocytosis and recruitment of T cells in the adventitia could contribute to the atheroprotection of Leukocyte ldlr deficiency and ABCA1.

关键词： ldl receptor ABCA1 lymphocytosis T lymphocytes atherosclerosis

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DETECTING LOW DENSITY LIPOPROTEIN receptor MUTANT GENE OF RABBIT BY PCR

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Journal of Pharmaceutical Analysis 2006年第2期18卷 199-201页

作者：刘恩岐赵四海陈正兰杨鹏辉 Laboratory Animal Center Xi'an Jiaotong University School of Medicine Xi'an 71006 China

Objective Watanabe Heritable Hyperlipidaemic (WHHL) rabbits with low density lipoprotein receptor (ldlr) gene mutation have provided unprecedented opportunities for the study of human atherosclerosis, in order to confirm ldl receptor gene status in rabbits, we developed a simple PCR technique to detect ldl mutations in rabbits. Methods Rabbits genomic DNA were extracted from ear biopsy, and amplified by PCR to detect 12bp deletion mutation in WHHL rabbits. PCR products were directly digested with BglⅠ, and then applied to polyacrylamide gel electrophoresis. Results PCR products from homozygous ldlr +/+ rabbits generated 2 bands of 212 and 94bp after BglⅠ digestion, ldlr +/- rabbits generated 3 bands (294, 212, and 94bp), ldlr -/- animals, however, generated only 1 product (294bp). Conclusion This modified PCR method is simple and reliable.

关键词： ldl receptor PCR rabbit

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Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C →T mutation of low-density lipoprotein receptor gene

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Chinese Medical Journal 2008年第9期121卷 776-781页

作者： LIN Jie WANG Lu-ya LIU Shu XIA Jun-hui YONG Qiang DU Lan-ping PAN Xiao-dong XUE Hong CHEN Bao-sheng JIANG Zhi-sheng Beijing Anzhen Hospital Capital Medical University Beijing Institute of Heart Lung and Blood Vessel Diseases Beijing 100029 China Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province University of South China Hengyang Hunan 421001 China Institute of Basic Medical Science Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100005 China

Background Familial hypercholesterolemia （FH）, caused by low density lipoprotein （ldl） receptor （ldl-R） gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel ldl-R gene mutation. Methods The patient＇s ldl-R gene coding region was sequenced. The patient＇s lymphocytes were isolated and the ldl-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient＇s heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging （MPI）. Results The patient＇s ldl-R expression, ldl binding and up-take functions were significantly lower than normal control （39%, 63% and 76% respectively）. A novel homozygous 1439 C→T mutation of the ldl-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes. Conclusions The ldl-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the ldl-R gene is determined. These data increase the mutational spectrum of FH in China.

关键词： familial hypercholesterolemia ldl receptor gene mutation gene function

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Mutation of Low-Density Lipoprotein receptor Gene and its Mutant Founction in a Chinese Familial Hypercholesterolemia Family

Mutation of Low-Density Lipoprotein Receptor Gene and its Mu...

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第四届全国血脂分析与临床学术研讨会暨第九届全国脂蛋白学术会议

作者： Pengyu Su Luya wang Jie Lin Shu Liu Junhui Xia Yingjie Xu Qiang Yong Ya Yang Xiaodong Pan Lanping Du Yanwen Qin Zhaosu Wu Department of Atherosclerosis,Beijing Institute of Heart Lung and Blood Vessel Diseases,Beijing Anzhen Hospital,Capital Medical University,Beijing 100029,China

Backround In China,about 1 million persons are expected to suffer from Familial hypercholesterolemia (FH) due to a simlilar to the prevalence of FH in whites,while the mutations underlying FH in China are large- ly unknown because there have been only a few studies. Aim In the present study,DNA sequencing analysis was used to scan the the low-density lipoprotein re- ceptor (ldlR) and apoB genes in a Chinese family with clinically diagnosed *** effect of this novel mu- tation on the function of ldlR was analyzed by construction of the mutant protein and by flow cytometry. Result The plasma total cholesterol levels of these patients ranged from 153.1 to 630.1 mg/dl and ldl cholesterol from 79.1 to 543.2 mg/dl without lipid-lowering drug *** DNA sequencing of the PCR products revealed that the proband was a compound heterozygote,with 1 mutation in exon 4 and 1 in exon 12 of the ldlR gene.A single base substitution (C for T) in exon 4 changes codon 152 in the mature protein from cysteine (UGC) to arginine (CGC).The other mutant allele has a single base pair substitution of A for C in the codon for residue 565 in exon 12,which introduces the change from serine (UCA) to a new stop codon (UAA).Amplification and sequencing of fragments of genomic DNA from the parents and sibling of the proband showed that the mother and father were heterozygous for the mutation in exon 4 and exon 12 respective- ly,while the brother was normal and had no mutations in the ldlR *** relatives from the maternal side were screened by PCR of exon 4 for the C152R *** results showed her aunt (Ⅱ:4) had the C152R mutation,the rest were *** 2 paternal relatives (Ⅰ:4 and Ⅱ:7) were not identified as having the $565X *** defective apoB (FDB) was excluded,as no mutation was detected in the PCR fragment of apoB100 according to the results of the DNA *** flow cytometry analysis,the p.S565X mutant receptor displays reduced binding and internalization

关键词： Familial hypercholesterolemia ldl receptor Nonsense mutation

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黄连生物碱对HepG2细胞和金黄地鼠的协同降胆固醇活性及机制研究

黄连生物碱对HepG2细胞和金黄地鼠的协同降胆固醇活性及机制研究

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作者：寇淑鸣西南大学

学位级别：硕士

心血管疾病是世界上的主要致死病因。众所周知,血脂异常是引发心血管疾病如冠心病,外周动脉疾病的主要危险因素之一,血脂异常指的是体内血清总胆固醇(TC),甘油三酯(TG),低密度脂蛋白水平(ldl-c)和高密度脂蛋白(HDL-c)水平的一种或者几... 详细信息

心血管疾病是世界上的主要致死病因。众所周知,血脂异常是引发心血管疾病如冠心病,外周动脉疾病的主要危险因素之一,血脂异常指的是体内血清总胆固醇(TC),甘油三酯(TG),低密度脂蛋白水平(ldl-c)和高密度脂蛋白(HDL-c)水平的一种或者几种发生异常。因此,改善血清脂质水平可以有效的干扰心血管疾病的进程。黄连具有抗菌、抗病毒、抗炎症、降血糖、降血脂等功效,小檗碱(BBR)、黄连碱(COP)、巴马汀(PAL)、表小檗碱(EPI)和药根碱(JAT)是黄连中主要的活性物质,它们具有相似的异喹啉结构,并且安全性相对较高。前期的研究表明这五种生物碱通过不同的分子机制展现出不同的降胆固醇活性。现在,针对治疗高血脂症的联合疗法被认为是一种新的治疗方案,它具有降脂作用活性高,用量少,副作用低等优势。因此,本实验研究,探索五种黄连生物碱(BBR,COP,PAL,JAT,EPI)对Hep G2细胞和金黄地鼠的协同降胆固醇活性和机制的研究。本实验研究的主要内容和结果:(1)在对数期Hep G2细胞生长状态良好的情况下,采用MTT实验检测不同浓度的黄连生物碱单体和复合物(COM)对细胞成活率的影响。结果表明,当BBR,COP,PAL,JAT,EPI和COM的浓度小于等于5μg/ml时,药物对Hep G2细胞成活率的影响很小,细胞成活率大于80%,没有明显毒性,所以,在当前实验条件下,BBR,COP,PAL,JAT,EPI和COM浓度均选择5μg/ml作为后续细胞实验的适宜浓度。(2)采用油红O染色法和HPLC分析法,探索比较黄连生物碱单体和复合物对高胆固醇诱导的Hep G2细胞的脂质积累和细胞内胆固醇水平的影响,结果表明,与生物碱单体组相比,COM能更有效的降低细胞内脂滴的积累和胆固醇水平。(3)初步探究黄连生物碱单体和复合物对高胆固醇诱导的Hep G2细胞中胆固醇代谢关键靶点的影响。利用q RT-PCR,western blot和免疫荧光的方法,检测Hep G2细胞中参与胆固醇代谢的关键基因ldl recptor,HMGCR和CYP7A1的表达。结果表明,与高胆固醇诱导组(HC)相比,五种生物碱单体和COM组能不同程度的增加ldl receptor和CYP7A1的表达,以及降低HMGCR的表达,尤其是COM组,与单体生物碱组相比,在调节胆固醇关键基因方面具有更明显的优势。(4)进一步探究比较黄连生物碱单体和复合物对金黄地鼠脂质水平的影响。检测金黄地鼠的血清指标(TC,TG,ldl-c,HDL-c)以及粪便中的TC和总胆汁酸(TBA)水平,结果表明,高脂高胆固醇诱导的金黄地鼠(HFHC)血清中TC,TG和ldl-c水平增加,HDL-c水平降低。给药处理后,与HFHC组相比,TC,TG和ldl-c水平得到显著的改善,相同剂量下,COM能分别显著降低TC 28.4%,TG 34.7%,ldl-c22.3%,相反,HDL-c水平显著增加。与单体组相比,COM能更有效的改善血清中的脂质水平。此外,与生物碱单体组相比,COM有效增加粪便中TC和TBA的排出。因此,可以得出,当五种主要生物碱以一定比例复配到一起时,其降胆固醇的活性显著提升。(5)为了进一步探究五种生物碱降胆固醇的协同效应,我们比较了BBR,COP,PAL,JAT,EPI和COM对金黄地鼠的血清和粪便中脂质指标的贡献率(CR),结果表明,在改善脂质水平方面,黄连生物碱复合物的贡献率大于生物碱单独使用的贡献率总和,说明黄连生物碱五种主要单体联合使用具有协同效应,能增强降胆固醇的活性。总的来说,黄连生物碱复合物在降低胆固醇方面具有协同效应,与黄连生物碱单体相比,具有更强的降胆固醇活性,其作用机制是上调ldl recptor和CYP7A1的表达,同时抑制HMGCR的表达。黄连生物碱联合疗法是一种治疗高胆固醇血症的潜在疗法。

关键词：黄连高胆固醇血症协同效应 ldl receptor CYP7A1

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