转录因子CREBZF调节肝脏糖异生和控制糖代谢平衡的机制研究

Uncontrolled hepatic glucose production is associated with hyperglycemia and type 2 diabetes. Hepatic gluconeogenesis is abnormality activated and contributes to hyperglycemia in diabetes. Recently, it is reported that AMPK enhances activity of CREBZF, and CREBZF strongly represses transcription of key gluconeogenic genes, including PGC1α, HNF4α, and CREBH, which prompt us to examine the general importance of this transcription factor for the regulation of the gluconeogenic program under fasting and diabetic conditions. The present project is aimed to gain insight into possible roles of CREBZF in controlling hepatic gluconeogenesis and maintaining whole body glucose homeostasis, using both in vivo and in vitro approaches. We hypothesize that AMPK phosphorylates and activates CREBZF to repress hepatic gluconeogenesis and control whole body glucose homeostasis. The applicants have well-established disease animal models and molecular reagents related to CREBZF. The significance of the project includes: a) uncover pathophysiological mechanisms of transcription factor CREBZF in regulating hepatic glucose homeostasis, and b) may provide a potential target for clinical intervention of hyperglycemia and diabetes.

糖尿病已成为21世纪威胁人类健康的主要因素，肝脏糖异生异常激活是造成高血糖和糖尿病的重要原因。最近研究发现，CREBZF能被AMPK激活，而且CREBZF能抑制糖异生途径的关键基因PGC1α、HNF4α以及CREBH等，表明CREBZF很可能参与调节糖代谢的过程。本项目旨在通过体内和体外实验，研究CREBZF在饥饿和糖尿病条件下对糖异生的调控，阐明CREBZF调节肝脏糖异生和维持全身糖代谢平衡的分子机制。我们推测，AMPK磷酸化并激活CREBZF，抑制肝脏糖异生，改善糖尿病。项目负责人已经构建了成熟的疾病动物模型和研究CREBZF所需的各种生物材料。本项目的意义在于，为临床干预高血糖和糖尿病提供的有效的药物靶标，为控制代谢病提供以CREBZF作为基因治疗靶点的新思路。

肥胖的发生可导致机体各器官出现胰岛素抵抗，而肝脏则会发生选择性抵抗。一方面胰岛素无法有效促进糖原合成，抑制糖异生，快速降糖；另一方面，其促进肝内脂质合成的作用只增不减，进而引发非酒精性脂肪肝，加剧机体的代谢失衡。而至今尚无明确的分子机制解释上述问题。本项目的研究内容主要围绕一种新型的转录因子CREBZF在肝脏脂质代谢调控的分子机制展开的。本项目研究结果发现当肝脏发生选择性胰岛素抵抗时，CREBZF的过度激活可能是造成肝脏脂质合成仍能持续进行的重要原因。该研究发现为非酒精性脂肪性肝病和胰岛素抵抗等代谢性疾病提供了新的治疗策略。在本基金的资助下，我们以唯一通讯作者在Hepatology（2篇）、Nature Communications、Journal of Biological Chemistry、Diabetes、Journal of visualized experiments等国际知名期刊发表多篇研究论文，申请PCT国际专利1项、中国发明专利2项；同时开展了广泛的国内外学术交流活动，多次在美国糖尿病会议（ADA）及国内代谢领域知名会议上做大会报告；培养多名博士及硕士研究生；各项经费均使用合理。我们的课题研究基本完成预定任务。