Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase.
Hepatitis B virus X protein regulates hepatic glucose homeostasis via activation of inducible nitric oxide synthase.
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DOI：
10.1074/jbc.m111.259978
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发表时间：
2011-08-26
期刊：
影响因子：
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通讯作者：
Yu DY
中科院分区：
文献类型：
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作者：
Shin HJ;Park YH;Kim SU;Moon HB;Park DS;Han YH;Lee CH;Lee DS;Song IS;Lee DH;Kim M;Kim NS;Kim DG;Kim JM;Kim SK;Kim YN;Kim SS;Choi CS;Kim YB;Yu DY
肝功能失调会导致胰岛素抵抗，从而导致 2 型糖尿病，并且常见于慢性肝病。然而，对于慢性肝病中肝功能障碍导致肝脏代谢紊乱的机制仍知之甚少。目前的工作研究了乙型肝炎病毒X蛋白（HBx）在调节葡萄糖代谢中的作用。我们研究了 HBx 过表达 (HBxTg) 小鼠和缺乏诱导型一氧化氮合酶 (iNOS) 的 HBxTg 小鼠。在这里，我们发现在表达 HBx 的 HepG2 细胞 (HepG2-HBx) 和高水平 HBx 表达的乙型肝炎病毒患者的非肿瘤肝组织中，关键糖异生酶的基因表达显着增加。在 HBxTg 小鼠的肝脏中，糖异生基因的表达也升高，通过增加肝脏葡萄糖的产生而导致高血糖。然而，这种作用不足以引起全身胰岛素抵抗。重要的是，HBx 对肝脏葡萄糖代谢的作用被认为是通过 iNOS 信号传导介导的，iNOS 缺乏通过抑制糖异生酶的基因表达来恢复 HBx 诱导的高血糖这一事实就证明了这一点。用一氧化氮 (NO) 处理 HepG2-HBx 细胞会导致糖异生基因的表达显着增加，但 JNK1 抑制完全正常化。此外，在缺乏 iNOS 的情况下，HBxTg 小鼠肝脏中 JNK1 的过度激活也受到抑制，这表明 JNK 在 HBx 和 iNOS 介导的葡萄糖代谢的相互调节中发挥着关键作用。这些发现建立了 HBx 驱动的肝脏代谢紊乱的新机制，该机制受 iNOS 介导的 JNK 激活调节。
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.