Molecular Mechanisms of Hepatitis C Virus- Associated Steatosis

Hepatitis C virus (HCV) infects millions of people worldwide and is one of the leading causes of liver damage. Infection with HCV is strongly correlated with an increased risk of steatosis, or fatty liver disease, which is caused by a build-up of fat deposits in hepatocytes. All genotypes of HCV appear to cause some degree of steatosis in approximately 50% of infected individuals, especially in the presence of contributing host factors such as diabetes, obesity and alcoholism. However, approximately 70% of genotype 3a infections exhibit steatosis. Furthermore, successful clearance of the genotype 3a virus results in eradication of the steatosis, suggesting the genotype 3a virus may be able to directly cause steatosis. Research suggests a role for the core protein of HCV, which forms the capsid of the virus, in the alteration of lipid metabolism pathways during infection. As such, I hypothesized that: 1) HCV alters lipid metabolism pathways and causes the build up of lipid in hepatocytes and the development of steatosis; 2) HCV-3a core protein has a differential or increased effect on these pathways in comparison to 1b core protein; and 3) other HCV proteins could also play a role in the altering of lipid metabolism. My research characterized the subcellular localization on lipid droplets of the HCV-3a core protein in comparison to HCV-1b core protein. It was found that HCV-3a core causes increased transcriptional activity from the Fatty Acid Synthase (FAS) promoter, an important enzyme involved in the synthesis of triglycerides in hepatocytes. In addition, one specific amino acid of HCV-3a core was determined to be partially responsible for this effect. Further research determined that the effect of HCV-3a core on FAS was dependent on the transcription factor Sterol Response Element Binding Protein-1 (SREBP-1) and the presence of HCV-3a core increased the processing and activity of SREBP-1. HCV core was also able to increase activity of Akt 1 and Akt2; inhibition of Akt activity resulted in decreased SREBP-1 activity thereby indicating that HCV core partially mediates SREBP-1 via Akt. Further experiments examined the role of another HCV protein, NS2, in these same lipid metabolism pathways. NS2 was also able to increase transcription from the FAS promoter via SREBP-1, suggesting that this HCV protein may also be important in the development of steatosis during HCV infection. The evidence provided in these studies shows a very important role for HCV in altering lipid metabolism during infection that may lead to the development of steatosis. Current research suggests that the SREBP-1 pathway may be critical in the life cycle of the virus and these studies have provided important information on how lipid metabolism pathways are being changed by the virus. Hopefully this work can help identify potential treatment options for HCV that can slow down disease progression by preventing the development of steatosis or by decreasing viral replication.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Veterinary Microbiology

Grantor

University of Saskatchewan

Year dc:date.issued

2009

Author dc:creator

• Jackel-Cram, Candice Marie

Advisor dc:contributor.advisor

• Liu, Qiang

• Hepatitis C Virus
• Cell Signalling
• Akt
• FAS
• SREBP
• Lipid Metabolism
• Steatosis

Language dc:language.iso

en_US

Handle dc:identifier.uri

https://hdl.handle.net/10388/etd-07312009-130703

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/etd-07312009-130703