Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids Vol. 1862; no. 7; pp. 692 - 705
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2017
• Subjects: Amino Acids - metabolism; Animals; Assemble; Cell Line; Cytosol - metabolism; Cytosol - virology; Cytosolic phospholipase A2 gamma; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - virology; Fatty Acids - metabolism; Group IV Phospholipases A2 - metabolism; HCV; HEK293 Cells; Hepacivirus - pathogenicity; Hepatitis C - metabolism; Hepatocytes - metabolism; Hepatocytes - virology; Humans; Lipid droplet; Lipid Droplets - metabolism; Lipid Droplets - virology; Lipid Metabolism - physiology; Liver - metabolism; Liver - virology; Male; Membranes - metabolism; Membranes - virology; Mice; Mice, Inbred C57BL; PLA2G4C; Steatosis; Lipid droplet; shRNA; NS; H&E; PLA2G4C; LD; HCV; Assemble; Cytosolic phospholipase A2 gamma; ER; ORO; Steatosis
• ISSN: 1388-1981; 1879-2618; 1879-2618
• DOI: 10.1016/j.bbalip.2017.03.007

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. •PLA2G4C is required for LD formation and translocated from ER to LD.•The membrane targeting and enzymatic activity of PLA2G4C are functional essential.•PLA2G4C overexpression enhanced LD accumulation in the liver of HFD-fed mice.