Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase |
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Authors: | Shin Hye-Jun Park Young-Ho Kim Sun-Uk Moon Hyung-Bae Park Do Sim Han Ying-Hao Lee Chul-Ho Lee Dong-Seok Song In-Sung Lee Dae Ho Kim Minhye Kim Nam-Soon Kim Dae-Ghon Kim Jin-Man Kim Sang-Keun Kim Yo Na Kim Su Sung Choi Cheol Soo Kim Young-Bum Yu Dae-Yeul |
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Institution: | Disease Model Research Laboratory, Aging Research Center and World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. |
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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. |
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Keywords: | Gluconeogenesis Hepatitis Virus Jun N-terminal Kinase (JNK) Metabolic Diseases Nitric Oxide Synthase |
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