DOI
https://doi.org/10.25772/C9ZN-0E81
Defense Date
2010
Document Type
Thesis
Degree Name
Master of Science
Department
Biochemistry
First Advisor
Barbour Suzanne
Abstract
Our recent studies have shown a link between Adenovirus-5 (Ad-5) and elevated lipids, which prompted the hypothesis that Ad-5 infection might augment hepatic and/or adipose tissue lipid metabolism. To test our hypothesis, mice were infected with Ad-5 and screened for changes in lipogenesis and plasma markers associated with the metabolic syndrome. We observed increased expression of sterol regulatory element binding protein 1 (SREBP-1) in infected liver tissues, but not in adipose tissues and this correlated with elevated plasma and hepatic triglyceride levels. Elevated expression of adiponectin was seen in Ad-5 infected adipose tissues and this correlated with phosphorylated AMPK in infected liver tissues. These data suggested that the AMPK pathway was activated in livers of Ad-5 infected mice. Indeed, we observed reduced expression of PEPCK, a downstream target of AMPK in livers of Ad-5 infected mice. As PEPCK is an enzyme essential for gluconeogenesis, we hypothesized that Ad-5 infection would reduce blood sugar. Indeed, infected mice exhibited a transient decline in plasma glucose. The increase in SREBP1 levels in Ad-5 infected hepatic tissues was evaluated by looking at Ad-5 infected HepG2 cells. Ad-5 is thought to mimic insulin’s actions in which the PI3K pathway is activated. We hypothesized that Ad5-induced SREBP-1 expression levels are mediated through the induction of PKC λ/ζ/ι, and not through Akt because it has been shown that PKC λ/ζ/ι mediates insulin-dependent lipogenesis. To test our hypothesis, HepG2 cells were infected with Ad-5 and screened for downstream targets of the PI3K pathway. Through western blot analyses, we observed increased levels of phosphorylated PKC λ/ζ/ι. These results prompted the use of PKC pan inhibitor to see whether Ad-5 induced SREBP-1 levels would be down regulated. Indeed, with the presence of the PKC pan inhibitor, SREBP-1 expression levels were reduced. Together, these studies suggest that Ad-5 induces changes in gene expression, glucose, and lipid metabolism; which prompts the hypothesis that this common respiratory pathogen may be associated with the Metabolic Syndrome, and this may preclude its use as a vector for gene therapy.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
December 2010