PMID:27155659

Citation	Barthel, SR, Medvedev, R, Heinrich, T, Büchner, SM, Kettern, N and Hildt, E (2016) Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor. Cell. Mol. Life Sci. 73:4121-40
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.
Links	PubMed Online version:10.1007/s00018-016-2259-1
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:NF2L2		GO:0010628: positive regulation of gene expression	ECO:0000315:		P		Figure 3b: knockdown of Nrf2 prevents tBHQ-induced expression of the IR (insulin receptor) gene	complete CACAO 12127
HUMAN:TXLNA		GO:1905476: negative regulation of protein localization to membrane	ECO:0000315:		P		Figure 5c: cells with elevated expression of alpha-taxilin show decreased binding of insulin to receptors on cell membrane, indicating decreased insulin receptors in the membrane.	complete CACAO 12128

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