HBx 诱发肝脏糖原代谢的昼夜节律性异常

在本文中，基于Hill 动力学与 Michaelis-Menten 方程，建立理论模型研究乙肝病毒x蛋白(HBx)诱发肝脏糖原代谢的昼夜节律性改变。理论模型考虑：HBx、组蛋白脱乙酰基酶1 (HDAC1) 与乙酰化的p53(p53AC) 结合形成复合体，并抑制 GYS2 表达；CLOCK 基因通过调控昼夜节律mRNA(Circadian mRNA)和频率蛋白(FRQ)的表达合成，调节 GYS2 磷酸化/去磷酸化的昼夜节律性。研究发现，在较低 HBx 浓度条件下，磷酸化的 GYS2 (pGYS2) 和去磷酸化的 GYS2 (dGYS2) 随时间演化，呈现了周期性的振荡特性。GYS2 通过磷酸化作用抑制其活性，通过去磷酸化，GYS2 被激活，这种磷酸化/去磷酸化转变保持了肝脏糖原代谢的昼夜节律性。在较高 HBx 浓度条件下，dGYS2 随时间演变的周期振荡节律性被改变，并且振荡幅度降低。由此表明，较高浓度的 HBx 则会在很大程度上改变 GYS2 去磷酸化的活性，GYS2 磷酸化/去磷酸化转变的昼夜节律性会被 HBx 破坏。另外，HBx 与 HDAC1、p53AC 形成复合体协同抑制 GYS2，也会在很大程度上改变 GYS2 磷酸化/去磷酸化转变的昼夜节律性。糖原代谢昼夜节律性的改变，导致肝脏内糖原代谢紊乱，进而促使肝癌(HCC)的发生发展。理论结果符合实验，并进一步揭示了 HBx 诱发肝脏糖原代谢紊乱，进而导致 HCC 的发生发展的一种致癌机理，可为设计阻断 HBV 向 HCC 转变通路的治疗方案提供理论依据。

Abnormal circadian rhythm of hepatic glycogen metabolism induced by HBx

In this paper, based on Hill kinetics and Michaelis-Menten equation, we built a theoretical model to study the circadian rhythm changes of hepatic glycogen metabolism induced by hepatitis B virus x protein (HBx). Theoretical model considerations: HBx, histone deacetylase 1 (HDAC1) and acetylated p53 (p53AC) combine to form a complex(HHP) and inhibit GYS2 expression. The CLOCK gene regulates the circadian rhythm of GYS2 phosphorylation/dephosphorylation by regulating the expression and synthesis of circadian mRNA (CmRNA) and frequency protein (FRQ). We found that at low HBx concentration, phosphorylated GYS2 (pGYS2) and dephosphorylated GYS2 (dGYS2) show periodic oscillation. GYS2 inhibits its activity through phosphorylation, and GYS2 is activated through dephosphorylation. This phosphorylation/dephosphorylation maintains the circadian rhythm of liver glycogen metabolism. At high HBx concentration, the periodic oscillation rhythm of dGYS2 is changed, and the oscillation amplitude is reduced. This indicates that a higher HBx concentration will greatly change the dephosphorylation activity of GYS2. Thus, the circadian rhythm of the phosphorylation/dephosphorylation transition of GYS2 will be disrupted by HBx. In addition, HBx forms a complex with HDAC1 and p53AC to inhibit the GYS2, which will also greatly regulate the circadian rhythm of the phosphorylation/dephosphorylation, and change the circadian rhythm of glycogen metabolism. The changes in the circadian rhythm of glycogen metabolism lead to disorders of glycogen metabolism in the liver, which in turn promotes the occurrence and development of hepatocellular carcinoma(HCC). The theoretical results are consistent with the experiment, and further reveal a carcinogenic mechanism that HBx induces liver glycogen metabolism disorders, which leads to the occurrence and development of HCC. It can provide a theoretical basis for the design of treatment plan that block the pathway from hepatitis B to HCC.