Mechanism of HDL Generation

HDL 生成机制

• 批准号: 14571104
• 负责人: ABE Sumiko
• 金额: $ 2.24万
• 依托单位: Nagoya City 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571104/
• 关键词: HDL; cholesterol; ABCA1; ABCA7; apolipoprotein

Various kinds of cell line cells were investigated for their response to lipid-free apolipoproteins to analyze the mechanism of apolipoprotein-mediated HDL generation. Major results are as follows.1.Change in apolipoprotein-mediated HDL generation in 293 cells expressing mutant ABCA1 cDNA found in Tangier's disease Patients is not identical, indicated that the mechanism of ABCA1-dependent HDL generation has several steps.2.There is a splicing variant (type II) cDNA of human ABCA7 and its tissue distribution and function in apo A-I-dependent lipid release is different from those of full length (type I) cDNA.3.Human ABCA7 (type I) supports apolipoprotein-mediated HDL generation from 293 cells as well as ABCA1 dose.4.Apolipoprotein A-I activates protein kinase C (presumably PKCα) and stabilizes ABCA1 protein in human fibroblast WI38 cells.5.Not lipidated but dissociated form of apolipoprotein A-I is essential for HDL generation from dBcAMP-treated RAW264,mouse macrophage-like cell line, cells.6.Verapamil and relative calcium channel blockers increases ABCA1 expression thorough LXR-independent mechanism and increases apoA-I-mediated HDL generation form dBcAMP-treated RAW264 cells.

通过研究各种细胞系细胞对无脂载脂蛋白的反应，分析载脂蛋白介导的HDL生成机制，主要结果如下： 1.发现表达突变ABCA1 cDNA的293细胞中载脂蛋白介导的HDL生成发生变化。在丹吉尔病患者中并不完全相同，表明ABCA1依赖性HDL生成的机制有几个步骤。 2.存在人ABCA7的剪接变体（II型）cDNA其在apo A-I依赖性脂质释放中的组织分布和功能与全长（I型）cDNA不同。3.人ABCA7（I型）支持载脂蛋白介导的293细胞和ABCA1剂量的HDL生成。4 .载脂蛋白 A-I 激活蛋白激酶 C（推测为 PKCα）并稳定人成纤维细胞 WI38 细胞中的 ABCA1 蛋白。5.非脂化但解离形式载脂蛋白 A-I 对于 dBcAMP 处理的 RAW264、小鼠巨噬细胞样细胞系、细胞的 HDL 生成至关重要。6.维拉帕米和相关钙通道阻滞剂通过 LXR 独立机制增加 ABCA1 表达，并增加 apoA-I 介导的 dBcAMP- 介导的 HDL 生成处理过的RAW264细胞。

项目成果

Yoshio Yamauchi, et al.: "Apolipoprotein A-I Activates Protein Kinase Ca Signaling to Phosphorylate and Stabilize ATP Binding Cassette Transporter Al for the High Density Lipoprotein Assembly"J.Biol.Chem.. 278. 47890-47897 (2003)

Yoshio Yamauchi 等人：“载脂蛋白 A-I 激活蛋白激酶 Ca 信号转导以磷酸化并稳定 ATP 结合盒转运蛋白 A1，用于高密度脂蛋白组装”J.Biol.Chem.. 278. 47890-47897 (2003)

Kei-ichiro Okuhira, et al.: "Potential involvement of dissociated apoA-l in the ABCA1-dependent cellular lipid release by HDL"J.Lipid Res.. 45. 645-652 (2004)

Kei-ichiro Okuhira 等人：“解离的 apoA-1 在 HDL 的 ABCA1 依赖性细胞脂质释放中的潜在参与”J.Lipid Res.. 45. 645-652 (2004)

Yamauchi Y, et al.: "Differential regulation of apolipoprotein A-I/ATP binding cassette transporter A1-mediated cholesterol and phospholipid release"Biochim.Biophys.Acta.. 1585. 1-10 (2002)

Yamauchi Y 等：“载脂蛋白 A-I/ATP 结合盒转运蛋白 A1 介导的胆固醇和磷脂释放的差异调节”Biochim.Biophys.Acta.. 1585. 1-10 (2002)

Shogo Suzuki, et al.: "Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by"Arterioscler Thromb Vasc Biol.. (in press). (2004)

Shogo Suzuki 等人：“维拉帕米通过动脉硬化血栓 Vasc Biol 增加载脂蛋白介导的细胞胆固醇释放”（正在印刷中）。

Kei-ichiro Okuhira, et al.: "Potential involvement of dissociated apoA-I in the ABCA1-dependent cellular lipid"J.Lipid Res.. 45. 645-652 (2004)

Kei-ichiro Okuhira 等人：“ABCA1 依赖性细胞脂质中解离的 apoA-I 的潜在参与”J.Lipid Res.. 45. 645-652 (2004)