Arylacetamide deacetylase: A novel host factor with important roles in the lipolysis of cellular triacylglycerol stores, VLDL assembly and HCV production

作者：Nourbakhsh Mahra; Douglas Donna N^*; Pu Christopher Hao; Lewis Jamie T; Kawahara Toshiyasu; Li**oa Luiz F; Wei Enhui; Asthana Sonal; Quiroga Ariel D; Law Lok Man John; Chen Chao; Addison William R; Nelson Randy; Houghton Michael; Lehner Richard; Kneteman Norman M

来源：Journal of Hepatology, 2013, 59(2): 336-343.

DOI：10.1016/j.jhep.2013.03.022

• Hepatitis C virus
• Very low density lipoprotein
• Lipid droplet
• Triacylglycerol hydrolase
• Activity-based protein profiling
• Arylacetamide deacetylase
• Triacylglycerol
• Apolipoprotein
• Hepatic lipid metabolism
• Carboxylesterase
• Lipase
• Serine esterase

Background & Aims: Very low density lipoproteins (VLDLs) are triacylglycerol (TG)-rich lipoproteins produced by the human liver. VLDLs derive the majority of their TG cargo from the lipolysis of TG stored in hepatocellular lipid droplets (LDs). Important roles for LDs and the VLDL secretory pathway in the cell culture production of infectious hepatitis C virus (HCV) have been established. We hypothesized that TG lipolysis and VLDL production are impaired during HCV infection so that these cellular processes can be diverted towards HCV production.
Methods: We used an HCV permissive cell culture system (JFH-1/HuH7.5 cells) to examine the relationship between TG lipolysis, VLDL assembly, and the HCV lifecycle using standard biochemical approaches.
Results: Upolysis of cellular TG and VLDL production were impaired in HCV infected cells during the early peak of viral infection. This was partially explained by an apparent deficiency of a putative TG lipase, arylacetamide deacetylase (AADAC). The reintroduction of AADAC to infected cells restored cellular TG lipolysis, indicating a role for HCV-mediated downregulation of AADAC in this process. Defective lipolysis of cellular TG stores and VLDL production were also observed in HuH7.5 cells stably expressing a short hairpin RNA targeting AADAC expression, proving AADAC deficiency contributes to these defective pathways. Finally, impaired production of HCV was observed with AADAC knock-down cells, demonstrating a role for AADAC in the HCV lifecycle.
Conclusions: This insight into the biology of HCV infection and possibly pathogenesis identifies AADAC as a novel and translationally relevant therapeutic target.

• 出版日期2013-8