Expression of the human apolipoprotein A-I: polymorphisms and drug effects

人载脂蛋白 A-I 的表达：多态性和药物作用

• 批准号: 14571115
• 负责人: MATSUNAGA Akira
• 金额: $ 1.86万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571115/
• 关键词: apohoonrotein A-I; apo1ipoprotein A-V; polymorphism; pitavastatin; hyperlipidemia; アポA-V; リポ蛋白; プロモーター; フェノフィブラート; 遺伝子異変

In course of apolipoprotein genes analysis, we found a polymorphism of APOA5 gene, c.553G>T in Japanese patients with hypertriglyceridemia. This polymorphism causes the change of amino acid substitution of a cysteine for a glycine. The frequencies of -1131T>C and c.553G>T polymoiphisms in 95 Japanese patients with hypertriglyceridemia and 119 unrelated normolipidemic subjects were determined by restriction-fragment-length-polymorphisms. The frequencies of the T allele at -1131bp (0.511) and the t allele at c.553G>T (0.205) in patients with hypertriglyceridemia were significantly higher than those in normolipidemic subjects (0.315 and 0.105), respectively (p<0.01and p<0.02). The two polymorphic sites were in strong linkage disequilibrium. These results suggest that the polymorphisms, -1131T>C and c.553G>T were associated with hypertriglyceridemia in Japanese population. Statin treatment reduces the levels of LDL cholesterol and triglyceride, and increases the levels of the antiatherogenic HDL. We investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Promoter activity of the APOA5 gene was estimated by measuring luciferase activity of plasmids with a APOA5 promoter region transfected into human hepatoma HepG2 cells. Treatment with pitavastatin significantly increased APOA5 expression and mRNA levels in human HepG2 cells, and cotransfection of a PPARa treatment resulted in a significant increase of APOA5 expression. These effects were reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, implicating HMG-CoA reductase as the relevant target of these drugs.

在载脂蛋白基因分析过程中，我们发现日本高脂血症患者存在载脂蛋白A5基因多态性，c.553G>T。这种多态性导致半胱氨酸对甘氨酸的氨基酸取代的变化。用限制性片段长度多态性方法测定了95例日本高脂血症患者和119例无关的正常血脂受试者的-1131 T>C和c.553 G>T多态性频率。高脂血症组-1131bp的T等位基因频率（0.511）和c.553G>T的t等位基因频率（0.205）分别显著高于血脂正常组（0.315和0.105）（p<0.01和p<0.02）。这两个多态性位点之间存在很强的连锁不平衡。这些结果表明，-1131 T>C和c.553 G>T多态性与日本人群的高血脂症有关。他汀类药物治疗降低了LDL胆固醇和甘油三酯的水平，并增加了抗动脉粥样硬化的HDL的水平。我们研究了它们调节APOA 5基因表达并因此影响血浆甘油三酯水平的能力。通过测量转染入人肝癌HepG 2细胞的具有APOA 5启动子区的质粒的荧光素酶活性来估计APOA 5基因的启动子活性。用匹伐他汀处理显著增加人HepG 2细胞中的APOA 5表达和mRNA水平，并且共转染PPARa处理导致APOA 5表达的显著增加。这些作用被逆转的甲羟戊酸或香叶基香叶基焦磷酸，暗示HMG-CoA还原酶作为这些药物的相关目标。

项目成果

Genetic analysis of Brugada syndrome in Western Japan: two novel mutations.

• DOI: 10.1253/circj.68.740
• 发表时间: 2004-07
• 期刊: Circulation journal : official journal of the Japanese Circulation Society
• 作者: Hideya Niimura;A. Matsunaga;K. Kumagai;K. Ohwaki;M. Ogawa;Hiroo Noguchi;K. Yonemura;K. Saku

Antioxidative effects of fluvastatin on superoxide anion activated by angiotensin II in human aortic smooth muscle cells.

氟伐他汀对人主动脉平滑肌细胞中血管紧张素 II 激活的超氧阴离子的抗氧化作用。

• 发表时间: 2002
• 期刊: Cardiovasc Drugs Ther 16
• 作者: Kugi M

Recombinant proapoA-I(hys107del) shows impaired lipid binding associated with reduced binding to plasma high density lipoprotein.

重组 proapoA-I(hys107del) 显示出与血浆高密度脂蛋白结合减少相关的脂质结合受损。

• 发表时间: 2001
• 期刊: Atherosclerosis 159
• 作者: Huang W

Associations among plasma lipoprotein subfractions as characterized by analytical capillary isotachophoresis, apolipoprotein E phenotype, Alzheimer disease, and mild cognitive impairment.

以分析毛细血管等速电泳、载脂蛋白 E 表型、阿尔茨海默病和轻度认知障碍为特征的血浆脂蛋白亚组分之间的关​​联。

• 发表时间: 2004
• 期刊: Arterioscler Thromb Vasc Biol. 24
• 作者: Shimabukuro M;Higa N;Takasu N;Tagawa T;Ueda S.;Zhang B
• 通讯作者: Zhang B

A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas.

载脂蛋白 A-I 基因（apoA-I Shinbashi）中的一个新的两个核苷酸缺失，与高密度脂蛋白缺乏、角膜混浊、平面黄瘤相关。

• 发表时间: 2004
• 期刊: Atherosclerosis 172
• 作者: Ikewaki K