The analysis of reverse cholesterol system in apolipoprotein A-1 deficiency

载脂蛋白A-1缺乏症的逆胆固醇系统分析

• 批准号: 13672414
• 负责人: TSUKAMOTO Kazuhisa
• 金额: $ 2.3万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672414/
• 关键词: Apolipoprotein A-1; HDL; reverse cholesterol transport; anti-oxidation; paraoxonase; atherosclerosis; Apolipoprotein E; oxidation stress; コレステロール逆転送; パラオキソナーゼ; パラオキソネース; アポリポタンパクA1欠損症

We experienced a 69-year-old Japanese woman with severely reduced levels of plasma HDL-cholesterol level (5 mg/dl), caused by apolipoprotein (apo) A-I deficiency. She was not symptomatic for coronary heart disease (CHD) despite the accumulated risks for CHD. Therefore, we analyzed not only the genomic DNA sequence, but also the characters of her lipid profile and the HDL-associated enzymes that are supposed to exert anti-atherogenic properties.The genomic DNA sequencing of apoA-I identified a cytosine deletion at the third base of codon 184 in the fourth exon, which theoretically led to a frame shift mutation and an early termination at codon 200. However, Western blot analysis did not reveal not only a normal apoA-I protein but also a mutant apoA-I protein. The HDL particles were rich in apoE, and the size of HDL particles rich in apoE was large, suggesting that these HDLs would facilitate cholesterol efflux.The activity of LCAT was only slightly reduced compared with normal controls despite no apoA-I in the plasma, and the protein levels of CETP was in normal ranges despite that this enzyme is proposed to be associated with HDL. Paraoxonase 1 (PON1) is an enzyme that is associated with HDL and exerts an anti-atherogenic property. It has been proposed that PON1 is stabilized with apoA-I on HDL, however, the PON1 protein distributed exclusively on HDL in our patient, while its stability in both the activity and localization on HDL was reduced. This instability in localization of PON1 protein on HDL might facilitate the delivery of PON1 protein to peripheral tissues through HDL particles, probably contributing to the protection from CHD in this patient.

我们经历了一名69岁的日本女性，其血浆HDL-胆固醇水平（5 mg/dl）严重降低，这是由载脂蛋白（APO）A-I缺乏症引起的。尽管冠心病的风险累积了，但她对冠心病（CHD）的症状并不是症状。 Therefore, we analyzed not only the genomic DNA sequence, but also the characters of her lipid profile and the HDL-associated enzymes that are supposed to exert anti-atherogenic properties.The genomic DNA sequencing of apoA-I identified a cytosine deletion at the third base of codon 184 in the fourth exon, which theoretically led to a frame shift mutation and an early termination at codon 200.但是，蛋白质印迹分析不仅揭示了正常的apoA-I蛋白，而且还没有揭示突变体apoa-a蛋白。 HDL颗粒富含APOE，并且富含APOE的HDL颗粒的大小很大，这表明这些HDL会促进胆固醇外排。尽管与血浆中的蛋白质水平在正常水平中，但与正常对照相比，LCAT的活性仅略有降低，并且与正常的ranges ranges相关。二氧酮酶1（PON1）是一种与HDL相关并具有抗动脉生育特性的酶。已经提出，PON1在HDL上用APOA-I稳定，但是，PON1蛋白在我们患者的HDL上仅分布在HDL上，而其在HDL的活性和本地化的稳定性均降低。 PON1蛋白在HDL上定位的这种不稳定性可能促进PON1蛋白通过HDL颗粒传递到外围组织，这可能有助于该患者的CHD保护。

项目成果

Noto H., Hashimoto Y., Tsukamoto K.et al.: "Exclusive Association of Paraoxonase 1 with HDL Particles in Apolipoprotein A-I Deficiency"Biochemical & Biophysical Research Communications. 289. 395-401 (2001)

Noto H.、Hashimoto Y.、Tsukamoto K.等人：“载脂蛋白 A-I 缺乏症中对氧磷酶 1 与 HDL 颗粒的专属关联”生物化学

Yokota H. Hashimoto Y. Okubo S. Yumoto M. Mashige F. Kawamura M. Kotani K. Usuki Y. Shimada S, Kitamura K. Nakahara K.: "Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms ; of CHD"Atherosclerosis. 162. 399-407 (2002)

Yokota H. Hashimoto Y. Okubo S. Yumoto M. Mashige F. Kawamura M. Kotani K. Usuki Y. Shimada S, Kitamura K. Nakahara K.：“载脂蛋白 A-I 缺乏会累积患 CHD 的风险，但没有症状；CHD”

Hiroshi Noto: "Exclusive association of paraoxonase 1 with HDL particles in apoA1 deficiency"Biochem Biophys Res Commun. 289. 395-401 (2001)

Hiroshi Noto：“apoA1 缺乏症中对氧磷酶 1 与 HDL 颗粒的独家关联”Biochem Biophys Res Commun。

Yokota H., Hashimoto Y., Yumoto M., Nakahara K.et al.: "Apolipoprotein A-I deficiency with accumulated risk for CUD but no symptoms of CHD"Atherosclerosis. 162. 399-407 (2002)

Yokota H.、Hashimoto Y.、Yumoto M.、Nakahara K.等人：“载脂蛋白 A-I 缺乏会累积 CUD 风险，但没有 CHD 症状”动脉粥样硬化。

Yokota H., Hashimoto Y., Yumoto M., Nakahara K.et al.: "Apolipoprotein A-I deficiency with accumulated risk for CHD but no symptoms of CHD"Atherosclerosis. 162. 399-407 (2002)

Yokota H.、Hashimoto Y.、Yumoto M.、Nakahara K.等人：“载脂蛋白 A-I 缺乏会累积患 CHD 的风险，但没有 CHD 症状”动脉粥样硬化。