Comprehensive study on the regulation of metabolism of lipids including long-chain fatty acids and very-long-chain faty acids

长链脂肪酸、超长链脂肪酸等脂质代谢调控综合研究

• 批准号: 11460044
• 负责人: AMACHI Teruo
• 金额: $ 6.85万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11460044/
• 关键词: fatty acids; cholesterol; phospholipids; ABC proteins; transporter; peroxisome; ABCA1; atherosclerosis; ATP; 遺伝子; クローニング; ベーター酸化

This study was done to understand the regulation of metabolism of lipids including long-chain fatty acids, very-long-chain fatty acids, phospholipids, and cholesterol from a comprehensive standpoint. The rate-determining step of catabolic pathway of long-chain fatty acids and very-long-chain fatty acids is the ATP- show high-affinity ATP binding and are co-precipitated together. The are also phosphorylated. Dimer formation could be regulated by ATP binding and/or phosphorylation.ABCA1 has been suggested to play a key role in cellular lipid release from peripheral cells. In orderto study structure-function relationship of this protein, the protein product of a full-length human ABCA1 cDNA was examined for its functions and topological oreintation. We suggested that the signal peptide in he amino-terminal region is cleaved off in its mature form and that the following large hydrophilic region is exposed to outside of cells unlike previously proposed models.We found that this amino-termibnal extracellular domain contains a segment homologous to he autoantigen SS-N, an epitope of Sjogren's syndrome, and further identified that ABCA7codes for the autoantigen SS-N.

本研究是为了从综合的角度了解长链脂肪酸、超长链脂肪酸、磷脂和胆固醇等脂质的代谢调节。长链脂肪酸和超长链脂肪酸分解代谢途径的限速步骤是ATP--表现出高亲和力的ATP结合并共同沉淀在一起。它们也被磷酸化。二聚体的形成受ATP结合和/或磷酸化的调节，ABCA 1在细胞脂质释放中起关键作用。为了研究该蛋白的结构与功能的关系，我们对人ABCA 1全长cDNA的蛋白产物进行了功能和拓扑结构分析。我们认为，与以前提出的模型不同，氨基端的信号肽在成熟时被切除，随后的大亲水区暴露在细胞外，我们发现这个氨基端的胞外区含有与Sjogren综合征的表位之一的自身抗原SS-N同源的片段，并进一步鉴定了ABCA_7编码的自身抗原SS-N。

项目成果

Tanaka, A.R.: "Human ABCA1 Contains a Large Amino-Terminal Extracellular Domain Homologous to an Epitope of Sjogren's Syndrome"Biochem. Biophys. Res. Commun.. 283. 1019-1025 (2001)

Tanaka, A.R.：“人类 ABCA1 含有与干燥综合征表位同源的大氨基末端细胞外结构域”Biochem。

Matsuo,M.: "Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy."J.Biol.Chem.. 275. 41184-41191 (2000)

Matsuo,M.：“突变型磺酰脲受体 SUR1-R1420C 的功能分析，该受体导致婴儿期持续性高胰岛素性低血糖。”J.Biol.Chem.. 275. 41184-41191 (2000)

植田和光: "ABCA1蛋白質の構造と機能."The Lipid. 13. 42-48 (2002)

Kazumitsu Ueda：“ABCA1 蛋白的结构和功能。”脂质。13. 42-48 (2002)

Ueda, K.: "Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide"Proc. Natl. Acad. Sci. USA. 96. 1268-1272 (1999)

Ueda, K.：“磺酰脲类受体中 ATP 和 MgADP 的协同结合受格列本脲调节”Proc.

Chen, Z.: "Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol a on MRP1 function"Int. J. Cancer. 93. 107-113 (2001)

Chen, Z.：“通过阿戈甾醇 a 对 MRP1 功能的双重作用逆转多药耐药蛋白 (MRP) 1 介导的耐药性”Int。