糖皮质激素通过DNA去甲基化酶Gadd45β促进肝脏糖异生的机制研究

糖皮质激素(Glucocorticoids, GCs)增多，可引起肝脏糖异生增加、肝糖输出增多，导致高血糖和胰岛素抵抗，但分子机制尚未明确。在前期工作中，通过对两种小鼠模型（地塞米松处理、饥饿小鼠）的肝脏组织进行RNA-Sequencing检测，并发现：DNA去甲基化酶Gadd45β显著上调，是GCs的重要靶基因。通过腺病毒系统，在小鼠肝脏上过表达Gadd45β，肝脏糖异生增强、血糖升高。机制研究则发现，Gadd45β过表达后，辅激活因子PGC1a的表达增加，从而促进糖异生关键酶PEPCK、G6Pase表达。因此，我们提出‘GCs-Gadd45β-PGC1a’调控轴，可能在肝脏糖异生和血糖稳态中，发挥重要的调节作用。本项目将在上述发现的基础上，进一步揭示GCs对Gadd45β的调控作用，并探讨Gadd45β调节肝脏糖异生的具体作用和机制，从而为2型糖尿病等代谢性疾病的防治提供新的科学依据。

The increase of glucocorticoids (GCs) can lead to the increase of hepatic gluconeogenesis, hepatic glucose output, hyperglycemia and insulin resistance, however, the molecular mechanism is still unclear. In our previous work, we detected RNA sequencing in the liver tissues of two mouse models (dexamethasone treated mice and fasting mice), and found that DNA demethylase Gadd45β was significantly upregulated, which was an important target gene of GCs. After overexpression of Gadd45β in the liver of mice through adenovirus system, gluconeogenesis and blood glucose in the liver were increased. The mechanism study demonstrated that the overexpression of Gadd45β increased the expression of PGC1α, which promoted the expression of PEPCK and G6Pase. Therefore, we suggest that GCs-Gadd45β- PGC1α may play an important role in liver gluconeogenesis and blood glucose homeostasis. Based on the above findings, this project will further reveal the regulatory effect of GCs on Gadd45β, and explore the specific role and mechanism of Gadd45β in regulating liver gluconeogenesis, thus provide a new scientific basis for the prevention and treatment of metabolic diseases such as type 2 diabetes.