title: Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase.
abstract: Dysregulation of liver functions leads to insulin resistance causing type 2 diabetes mellitus and is often found in chronic liver diseases. However, the mechanisms of hepatic dysfunction leading to hepatic metabolic disorder are still poorly understood in chronic liver diseases. The current work investigated the role of hepatitis B virus X protein (HBx) in regulating glucose metabolism. We studied HBx-overexpressing (HBxTg) mice and HBxTg mice lacking inducible nitric oxide synthase (iNOS). Here we show that gene expressions of the key gluconeogenic enzymes were significantly increased in HepG2 cells expressing HBx (HepG2-HBx) and in non-tumor liver tissues of hepatitis B virus patients with high levels of HBx expression. In the liver of HBxTg mice, the expressions of gluconeogenic genes were also elevated, leading to hyperglycemia by increasing hepatic glucose production. However, this effect was insufficient to cause systemic insulin resistance. Importantly, the actions of HBx on hepatic glucose metabolism are thought to be mediated via iNOS signaling, as evidenced by the fact that deficiency of iNOS restored HBx-induced hyperglycemia by suppressing the gene expression of gluconeogenic enzymes. Treatment of HepG2-HBx cells with nitric oxide (NO) caused a significant increase in the expression of gluconeogenic genes, but JNK1 inhibition was completely normalized. Furthermore, hyperactivation of JNK1 in the liver of HBxTg mice was also suppressed in the absence of iNOS, indicating the critical role for JNK in the mutual regulation of HBx- and iNOS-mediated glucose metabolism. These findings establish a novel mechanism of HBx-driven hepatic metabolic disorder that is modulated by iNOS-mediated activation of JNK.
authors.affiliation: Disease Model Research Laboratory, Aging Research Center and World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Hye-Jun
authors.initials: HJ
authors.lastname: Shin
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Sun-Uk
authors.initials: SU
authors.lastname: Kim
authors.forename: Hyung-Bae
authors.initials: HB
authors.lastname: Moon
authors.forename: Do Sim
authors.initials: DS
authors.lastname: Park
authors.forename: Ying-Hao
authors.initials: YH
authors.lastname: Han
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
authors.forename: In-Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Minhye
authors.initials: M
authors.lastname: Kim
authors.forename: Nam-Soon
authors.initials: NS
authors.lastname: Kim
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Sang-Keun
authors.initials: SK
authors.lastname: Kim
authors.forename: Yo Na
authors.initials: YN
authors.lastname: Kim
authors.forename: Su Sung
authors.initials: SS
authors.lastname: Kim
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
mesh_terms: D000818:Animals; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000096:biosynthesis* / Q000235:genetics; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008099:Liver / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D005947:Glucose