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Dissertation
Interplay of hepatitis B virus infection and hepatocyte metabolism: a virus-induced Warburg-like effect stimulates hepatitis B virus replication
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2021
DOI:
https://doi.org/10.17918/00000694
Abstract
The worldwide number of deaths due to viral hepatitis rose to 1.4 million in 2016, surpassing deaths caused by human immunodeficiency virus, malaria, or tuberculosis. A major cause of hepatitis is a hepatitis B virus (HBV) infection. Chronic HBV infections are a major global health issue, with an estimated 257 million people currently living with a chronic HBV infection and at risk for developing HBV-associated liver diseases. Due to HBV-vaccination drives by the World Health Organization, the occurrence of new HBV infections has been reduced in many parts of the world; however, vaccine availability and cost, as well as problems with transportation of the vaccine to remote or impoverished communities, have left millions unvaccinated. There are various anti-HBV therapies available; however, because none of these therapies target an HBV replication intermediate referred to as the HBV covalently closed circular DNA, these therapies typically do not cure the infection. Chronic HBV infection is a leading cause of hepatocellular carcinoma (HCC), the fourth most prevalent cause of deaths related to cancer worldwide. Although, the molecular mechanisms that link an HBV infection to HCC are not fully understood, recent studies indicate that HBV-induced alterations of cellular metabolism could be one factor that affects hepatocyte transformation. To understand the interplay of an HBV infection and hepatocyte physiology, we assessed HBV effects on metabolism and physiology using cultured primary rat hepatocytes (PRHs), cultured primary human hepatocytes (PHHs), mice with humanized livers, and a novel 3-dimensional hepatocyte co-culture model. Previously, we showed that expression of hypoxia-inducible factor (HIF)1[alpha], a component of the HIF1 transcription factor, enhances the level of HBV mRNAs, nucleocapsids, and genome replication in human hepatoblastoma HepG2 cells, which have stable expression of HIF1[beta], the other component of HIF1. Here, we report that HIF1 upregulates HBV core protein expression and genome replication in PRHs. Interestingly, HBV also elevated Pyruvate Kinase M2 (PKM2) mRNA, protein expression, and localization to the nucleus. PKM2 is typically upregulated in transformed cells where it can activate transcription of genes such as HIF1[alpha] and the glucose transporter GLUT1. We show that HBV infection increases expression of GLUT1 and glucose uptake and that siRNA-mediated knockdown of PKM2 and GLUT1 diminished HBV core protein expression and genome replication. Overall, these studies show that HBV activates PKM2, and that HBV replication is regulated by PKM2 and HIF1. HBV activation of PKM2 could also influence development of HBV-associated liver diseases, including HCC, and could be a novel anti-HBV therapeutic target.
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Details
- Title
- Interplay of hepatitis B virus infection and hepatocyte metabolism
- Creators
- Ronak Subhash Loonawat
- Contributors
- Michael Bouchard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 323 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014972849004721