title: Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor.
abstract: Hepatitis B virus (HBV) causes severe liver disease but the underlying mechanisms are incompletely understood. During chronic HBV infection, the liver is recurrently injured by immune cells in the quest for viral elimination. To compensate tissue injury, liver regeneration represents a vital process which requires proliferative insulin receptor signaling. This study aims to investigate the impact of HBV on liver regeneration and hepatic insulin receptor signaling. After carbon tetrachloride-induced liver injury, liver regeneration is delayed in HBV transgenic mice. These mice show diminished hepatocyte proliferation and increased expression of fibrosis markers. This is in accordance with a reduced activation of the insulin receptor although HBV induces expression of the insulin receptor via activation of NF-E2-related factor 2. This leads to increased intracellular amounts of insulin receptor in HBV expressing hepatocytes. However, intracellular retention of the receptor simultaneously reduces the amount of functional insulin receptors on the cell surface and thereby attenuates insulin binding in vitro and in vivo. Intracellular retention of the insulin receptor is caused by elevated amounts of α-taxilin, a free syntaxin binding protein, in HBV expressing hepatocytes preventing proper targeting of the insulin receptor to the cell surface. Consequently, functional analyses of insulin responsiveness revealed that HBV expressing hepatocytes are less sensitive to insulin stimulation leading to delayed liver regeneration. This study describes a novel pathomechanism that uncouples HBV expressing hepatocytes from proliferative signals and thereby impedes compensatory liver regeneration after liver injury.
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Sebastian Robert
authors.initials: SR
authors.lastname: Barthel
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Medvedev
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Thekla
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Sarah Manon
authors.initials: SM
authors.lastname: Büchner
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Kettern
authors.affiliation: Department of Virology, Paul-Ehrlich-Institut, Langen, Germany. eberhard.hildt@pei.de.|German Center for Infection Research (DZIF), Gießen-Marburg-Langen, Gießen, Germany. eberhard.hildt@pei.de.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Hildt
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008115:Liver Regeneration / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D051267:NF-E2-Related Factor 2; D033921:Vesicular Transport Proteins; D011972:Receptor, Insulin
keywords: HBV; Insulin receptor signaling; Insulin resistance; Liver disease; Nrf2; α-Taxilin