Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation
Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation
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脂滴形成中胞质磷脂酶 A2 γ 的需要
DOI：
10.1016/j.bbalip.2017.03.007
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发表时间：
2017
影响因子：
4.8
通讯作者：
Chen Xinwen
中科院分区：
文献类型：
--
作者：
Su Xi;Liu Shuhui;Zhang Xianwen;Lam Sin Man;Hu Xue;Zhou Yuan;Chen Jizheng;Wang Yun;Wu Chunchen;Shui Guanghou;Lu Mengji;Pei Rongjuan;Chen Xinwen
肝细胞内脂质滴（LD）的积聚是脂肪变性的典型特征。丙型肝炎病毒（HCV）感染，与脂肪变性的危险因素之一，诱导LD在培养细胞中的积累。然而，HCV诱导LD形成的机制尚未完全揭示。以前，我们确定胞浆磷脂酶A2 γ（PLA 2G 4C）作为宿主因子上调HCV感染和参与HCV复制。本研究进一步揭示了PLA 2G 4C在LD生物发生中的重要作用，并完善了PLA 2G 4C在LD生物发生和HCV组装中的功能分析。在PLA 2G 4C敲低细胞中，脂肪酸和HCV刺激后LD形成受损，并且不能通过与PLA 2G 4A互补来恢复。PLA 2G 4C在膜中与氨基酸残基260-292周围的结构域紧密相关，通常在ER中，但在油酸盐刺激后重新定位到LD中。没有酶活性的突变体PLA 2G 4C不能恢复PLA 2G 4C敲低细胞中LD的形成。因此，膜附着和酶活性的PLA 2G 4C所需的LD形成的功能。PLA 2G 4C参与LD形成与其参与HCV组装相关。最后，PLA 2G 4C过表达本身导致LD在肝细胞中形成，并增强LD在高脂饮食（HFD）喂养小鼠肝脏中的积累，表明其在脂肪肝疾病中的潜在作用。
Lipid droplet (LD) accumulation in hepatocytes is a typical character of steatosis. Hepatitis C virus (HCV) infection, one of the risk factors related to steatosis, induced LD accumulation in cultured cells. However, the mechanisms of which HCV induce LD formation are not fully revealed. Previously we identified cytosolic phospholipase A2 gamma (PLA2G4C) as a host factor upregulated by HCV infection and involved in HCV replication. Here we further revealed that PLA2G4C plays an important role in LD biogenesis and refined the functional analysis of PLA2G4C in LD biogenesis and HCV assembly. LD formation upon fatty acid and HCV stimulation in PLA2G4C knockdown cells was impaired and could not be restored by complementation with PLA2G4A. PLA2G4C was tightly associated in the membrane with the domain around the amino acid residues 260–292, normally in ER but relocated into LDs upon oleate stimulation. Mutant PLA2G4C without enzymatic activity was not able to restore LD formation in PLA2G4C knockdown cells. Thus, both the membrane attachment and the enzymatic activity of PLA2G4C were required for its function in LD formation. The participation of PLA2G4C in LD formation is correlated with its involvement in HCV assembly. Finally, PLA2G4C overexpression itself led to LD formation in hepatic cells and enhanced LD accumulation in the liver of high-fat diet (HFD)-fed mice, suggesting its potential role in fatty liver disease.