Global analysis of HBV-mediated changes to the primary hepatocyte transcriptome and metabolome

Abstract

Chronic infection with hepatitis B virus (HBV) remains a significant health concern, with between 350-500 million people chronically infected worldwide. Approximately 25% of chronically infected individuals will go on to develop HBVassociated hepatocellular carcinoma (HCC), making chronic infection with HBV the leading risk factor for developing HCC. With the high incidence and mortality of HCC, it is important to fully understand the mechanisms that lead to the development of HBV-associated HCC. HBV requires a complex network of hostvirus interactions to meet its requirements for successful replication. Each of these host-virus interactions, over a decades-long chronic infection, could significantly alter the physiology of an infected hepatocyte, the target of HBV infection, and ultimately contribute to the oncogenic potential of HBV. Typically, studies of these host-virus interactions have focused on a single factor or pathway to characterize contributions to HBV replication or HBV-associated disease, but these studies have generally not considered hepatocyte physiology as a whole. We hypothesized that using broad, transcriptomic- and metabolomic -based technologies would allow us to establish a better understanding of the complexity of the host-virus interaction mediated by HBV and how an HBV infection affects overall hepatocyte physiology. To achieve this, we utilized an ex-vivo primary rat hepatocyte model and defined transcriptome-wide, HBV-mediated changes to gene expression. We also utilized metabolomic profiling to assess the impact of HBV, and the HBV X protein (HBx), on overall hepatocyte metabolism and correlated these changes to HBV-mediated changes in gene expression. Using this approach, we identified significant alterations of many genes and pathways central to hepatocyte physiology, including cell cycle regulation, lipid metabolism, and energy metabolism. Our results simultaneously identified multiple HBV-mediated changes to hepatocyte physiology, increasing our understanding of the complex relationship between HBV and an infected hepatocyte. Additionally, the identification of HBV-regulated genes will serve as the basis for future studies in understanding the physiological impact of an HBV infection. Together, these findings will allow a better understanding of HBV-mediated affects on hepatocyte physiology that could ultimately contribute to the development of HBV-associated disease, potentially guiding the generation of novel therapeutics and strategies to prevent HBV-associated HCC.%%%%Ph.D., Microbiology and Immunology – Drexel University, 2015