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Phenobarbital Inactivates Insulin Receptor to Elicit CAR‐dependent Decrease or –Independent Increase of Hepatic Gluconeogenesis
Author(s) -
Yasujima Tomoya,
Moore Rickie,
Negishi Masahiko
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.934.9
Subject(s) - foxo1 , gluconeogenesis , dephosphorylation , insulin receptor , chemistry , protein kinase b , endocrinology , medicine , receptor , constitutive androstane receptor , insulin , transcription factor , nuclear receptor , signal transduction , phosphorylation , biology , metabolism , biochemistry , insulin resistance , phosphatase , gene
Nuclear receptor CAR (constitutive active/androstane receptor, NR1I3) is a transcription factor activated by various drugs such as phenobarbital (PB). Upon activation, CAR suppresses hepatic gluconeogenesis as well as induces drug metabolism. Recently,epidermal growth factor receptor (EGFR) was characterized as an initial target of PB to elicit the cellular signal that activates CAR (Mutoh et al., Sci Signal. 6 , ra31, 2013). Since PB is known to antagonize insulin receptor (IR) (Hwang et al., Biochem Biophys Res Commun. 135 , 501‐6, 1986), here we have examined whether or not PB regulates CAR and/or gluconeogenesis through IR. PB treatment dephosphorylated IR in human hepatoma‐derived HepG2 and in mouse primary hepatocytes. This dephosphorylation appeared to be caused by PB binding to IR as indicated by competitive binding assays using 125 I‐insulin. PB‐induced dephosphorylation resulted in inactivation of the down‐stream signal molecules RACK1, ERK1/2, AKT and FOXO1. Inactivation of RACK1 and ERK1/2 is consistent with CAR‐mediated repression of gluconeogenesis (Kodama et al., Mol Cell Biol. 24 , 7931‐40, 2004) whereas that of AKT and FOXO1 can be a PB signaling that suppressed gluconeogenesis in CAR‐independent manner. Utilizing CAR KO mice, we have now been investigating to demonstrate that blood glucose levels are, in fact, regulated by these CAR‐dependent and –independent mechanisms in the livers in vivo .