CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells
CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells
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DOI：
10.1194/jlr.m700279-jlr200
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发表时间：
2007-10-01
影响因子：
6.5
通讯作者：
Yu, Liqing
中科院分区：
文献类型：
--
作者：
Brown, J. Mark;Chung, Soonkyu;Yu, Liqing
比较基因鉴定-58（CGI-58）是蛋白质的α/β-水解酶家族的成员。人类CGI-58基因的突变与Chanarin-Dorfman综合征相关，Chanarin-Dorfman综合征是一种罕见的常染色体隐性遗传病，其中多个组织中发生过度甘油三酯（TG）积累。在这项研究中，我们研究了CGI-58在几种细胞模型中的细胞脂质代谢中的作用，并发现CGI-58在促进肝癌细胞中细胞质TG包装成分泌的脂蛋白颗粒中的作用。使用功能获得和功能丧失方法，我们证明CGI-58促进细胞TG储存的消耗，而不改变细胞胆固醇或磷脂的积累。这种细胞TG的消耗仅归因于增强的水解，而TG合成不受CGI-58的影响。此外，CGI-58介导的TG水解可以被已知的脂肪酶抑制剂磷酸二乙伞形酮酯和磷酸二乙-对-硝基苯酯完全抑制，但不能被对-氯-汞苯甲酸酯抑制。有趣的是，CGI-58驱动的TG水解与脂肪酸氧化和TG分泌的增加相结合。总的来说，这项研究揭示了CGI-58在将细胞质TG的脂解降解偶联到氧化和包装成富含TG的脂蛋白以在肝癌细胞中分泌中的作用。
Comparative Gene Identification-58 (CGI-58) is a member of the alpha/beta-hydrolase family of proteins. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman syndrome, a rare autosomal recessive genetic disease in which excessive triglyceride (TG) accumulation occurs in multiple tissues. In this study, we investigated the role of CGI-58 in cellular lipid metabolism in several cell models and discovered a role for CGI-58 in promoting the packaging of cytoplasmic TG into secreted lipoprotein particles in hepatoma cells. Using both gain-of-function and loss-of-function approaches, we demonstrate that CGI-58 facilitates the depletion of cellular TG stores without altering cellular cholesterol or phospholipid accumulation. This depletion of cellular TG is attributable solely to augmented hydrolysis, whereas TG synthesis was not affected by CGI-58. Furthermore, CGI-58-mediated TG hydrolysis can be completely inhibited by the known lipase inhibitors diethylumbelliferyl phosphate and diethyl-p-nitrophenyl phosphate, but not by p-chloro-mercuribenzoate. Intriguingly, CGI-58-driven TG hydrolysis was coupled to increases in both fatty acid oxidation and secretion of TG. Collectively, this study reveals a role for CGI-58 in coupling lipolytic degradation of cytoplasmic TG to oxidation and packaging into TG-rich lipoproteins for secretion in hepatoma cells.