Adipose triglyceridelipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome
Adipose triglyceridelipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome
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DOI：
10.1016/j.cmet.2006.03.005
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发表时间：
2006-05-01
期刊：
影响因子：
29
通讯作者：
Zechner, Rudolf
中科院分区：
文献类型：
--
作者：
Lass, Achim;Zimmermann, Robert;Zechner, Rudolf
脂肪甘油三酯脂肪酶（ATGL）是一种重要的三酰甘油（TG）水解酶，促进脂肪和非脂肪组织中储存脂肪的分解代谢。我们现在证明，有效的ATGL酶活性需要CGI-58激活。人类CGI-58基因突变与Chanarin-Dorfman综合征（CDS）有关，这是一种罕见的遗传病，TG在多个组织中过度积累。CGI-58与ATGL相互作用，刺激其TG水解酶活性高达20倍。携带与CDS相关的点突变的CGI-58等位基因不能激活ATGL。此外，CGI-58/ATGL共表达可减轻COS-7细胞中的脂质积累。反义rna介导的3T3-L1脂肪细胞中CGI-58表达降低抑制TG动员。最后，功能性CGI-58在CDS成纤维细胞中的表达恢复了脂肪分解，逆转了CDS典型的异常TG积累。这些数据证实了CGI-58在脂肪的脂解降解中具有重要的生化功能，暗示这种脂解激活剂参与了CDS的发病机制。
Adipose triglyceride lipase (ATGL) was recently identified as an important triacylglycerol (TG) hydrolase promoting the catabolism of stored fat in adipose and nonadipose tissues. We now demonstrate that efficient ATGL enzyme activity requires activation by CGI-58. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman Syndrome (CDS), a rare genetic disease where TG accumulates excessively in multiple tissues. CGI-58 interacts with ATGL, stimulating its TG hydrolase activity up to 20-fold. Alleles of CGI-58 carrying point mutations associated with CDS fail to activate ATGL. Moreover, CGI-58/ATGL coexpression attenuates lipid accumulation in COS-7 cells. Antisense RNA-mediated reduction of CGI-58 expression in 3T3-L1 adipocytes inhibits TG mobilization. Finally, expression of functional CGI-58 in CDS fibroblasts restores lipolysis and reverses the abnormal TG accumulation typical for CDS. These data establish an important biochemical function for CGI-58 in the lipolytic degradation of fat, implicating this lipolysis activator in the pathogenesis of CDS.