title: Hepatitis B virus (HBV) X protein-mediated regulation of hepatocyte metabolic pathways affects viral replication.
abstract: Chronic HBV infection is a risk factor for hepatocellular carcinoma (HCC). The HBV HBx protein stimulates HBV replication and likely influences the development of HBV-associated HCC. Whether HBx affects regulators of metabolism in normal hepatocytes has not been addressed. We used an ex vivo, cultured primary rat hepatocyte system to assess the interplay between HBV replication and mechanistic target of rapamycin complex 1 (mTORC1) signaling. HBx activated mTORC1 signaling; however, inhibition of mTORC1 enhanced HBV replication. HBx also decreased ATP levels and activated the energy-sensing factor AMP-activated protein kinase (AMPK). Inhibition of AMPK decreased HBV replication. Inhibition of AMPK activates mTORC1, and we showed that activated mTORC1 is one factor that reduces HBV replication when AMPK is inhibited. HBx activation of both AMPK and mTORC1 suggests that these activities could provide a balancing mechanism to facilitate persistent HBV replication. HBx activation of mTORC1 and AMPK could also influence HCC development.
authors.affiliation: Graduate Program in Molecular and Cellular Biology and Genetics, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Philadelphia, PA, United States.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Bagga
authors.affiliation: Graduate Program in Molecular and Cellular Biology and Genetics, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Philadelphia, PA, United States.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Rawat
authors.affiliation: Facultad de Ciencias Biosanitarias, Universidad Franscisco de Vitoria, Madrid, Spain; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, United States.
authors.forename: Marcia
authors.initials: M
authors.lastname: Ajenjo
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, United States. Electronic address: michael.bouchard@drexelmed.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bouchard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006509:Hepatitis B / Q000378:metabolism / Q000821:virology; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D053858:Metabolic Networks and Pathways; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
chemical_list: D046912:Multiprotein Complexes; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Hepatitis B Virus; Hepatocellular carcinoma; Metabolism; Primary hepatocyte; Viral replication; Viruses; mTORC1