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Role of TG Lipases, Arylacetamide Deacetylase and Triacylglycerol Hydrolase, in Hepatitis C Virus Life Cycle Open Access


Other title
Hepatitis C Virus
Triacylglycerol Hydrolase
Very Low Density Lipoprotein
Arylacetamide Deacetylase
Type of item
Degree grantor
University of Alberta
Author or creator
Nourbakhsh, Mahra
Supervisor and department
Kneteman, Norman (Department of Surgery)
Douglas, Donna (Department of Surgery)
Examining committee member and department
Lehner, Richard (Department of Pediatrics)
babiuk, Lorne (VP-Research, University of Alberta)
Houghton, Michael (Department of Medical Microbiology and Immunology)
Richardson, Christopher (Department of Microbiology and Immunology, Dalhousie University)
Department of Surgery
Experimental Surgery
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Hepatitis C virus (HCV) is a major cause of chronic liver disease, including liver steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. It has become apparent that the targeting of lipid droplets (LDs) by the HCV core protein and the Very Low Density Lipoprotein (VLDL) secretory pathway play important roles in the HCV lifecycle. VLDL is a triacylglycerol (TG) rich lipoprotein particle that acquires the majority of its fat cargo from the preformed TG that is stored in LDs. Therefore we hypothesize that during HCV infection the VLDL assembly/secretory process would be diverted in order to support productive viral infection. This possibility is intriguing since hepatic steatosis, characterized by hepatocellular accumulation of LDs, is a common clinical finding of HCV infection and impaired VLDL assembly/secretion characterized by hypobetalipoproteinemia is associated with chronic HCV infection. We used Huh7.5/JFH-1 cell culture system to examine the relationship between HCV life cycle and VLDL secretory pathway. Using standard biochemical approaches, we have examined the key regulators of VLDL secretory pathway during HCV infection. In particular, the contribution of two putative TG lipases, arylacetamide deacetylase (AADAC) and triacylglycerol hydrolase (TGH) to the lipolytic mobilization of cellular TG stores for secretion with VLDL were examined. These studies demonstrate that the lipolysis 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 for AADAC. The re-introduction of AADAC to infected cells restored cellular TG lipolysis, indicating a role for HCV-mediated downregulation of AADAC in this process. Silencing of AADAC in naïve cells confirmed that endogenous AADAC indeed plays a role in the lipolysis of cellular TG stores and in the addition of lipid to nascent VLDL. TGH was absent from Huh7.5 cells and although its re-introduction to non-infected cells enhanced the mobilization of cellular TG for secretion with VLDL and VLDL production, it was not able to restore the defective cellular TG lipolysis due to AADAC deficiency in infected cells. Finally, impaired production of HCV was observed with the AADAC knockdown cells, demonstrating a role for AADAC in the HCV lifecycle.
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