Lass Achim, Zimmermann Robert, Haemmerle Guenter, Riederer Monika, Schoiswohl Gabriele, Schweiger Martina, Kienesberger Petra, Strauss Juliane G, Gorkiewicz Gregor, Zechner Rudolf
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Cell Metab. 2006 May;3(5):309-19. doi: 10.1016/j.cmet.2006.03.005.
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.
脂肪甘油三酯脂肪酶（ATGL）最近被确定为一种重要的甘油三酯（TG）水解酶，可促进脂肪组织和非脂肪组织中储存脂肪的分解代谢。我们现在证明，高效的ATGL酶活性需要CGI-58激活。人类CGI-58基因的突变与钱纳林-多夫曼综合征（CDS）相关，这是一种罕见的遗传病，其中TG在多个组织中过度积累。CGI-58与ATGL相互作用，将其TG水解酶活性提高多达20倍。携带与CDS相关的点突变的CGI-58等位基因无法激活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表达的降低抑制了TG的动员。最后，在CDS成纤维细胞中功能性CGI-58的表达恢复了脂解作用，并逆转了CDS典型的异常TG积累。这些数据确立了CGI-58在脂肪脂解降解中的重要生化功能，表明这种脂解激活剂与CDS的发病机制有关。
