Metabolic Regulation of Gene Expression by AMP-Kinase

说明(申请人提供)：AMP激活蛋白激酶(AMPK)是信号系统的中心组成部分，其功能是维持细胞能量平衡，以应对耗尽细胞内ATP的压力。它通常被称为“代谢总开关”，因为它在维持代谢平衡中起着核心作用。AMPK活性对全身糖代谢的调节有很强的影响，也可能在2型糖尿病的发生发展中发挥作用。最近报道，药物二甲双胍和激素脂联素的一些抗糖尿病活性可能是通过激活肝脏中的AMPK来介导的，这表明AMPK与肝脏的葡萄糖代谢之间存在潜在的联系。我们最近证明，转录因子HNF4pha是肝脏代谢基因表达的调节因子，可被AMPK介导的丝氨酸-304磷酸化抑制。已知HNF4α在参与调节肝脏葡萄糖产生的肝脏基因的表达中发挥重要作用，而肝脏葡萄糖产生是正常和糖尿病全身葡萄糖平衡的关键因素。这项工作的中心假设是，肝脏中的AMPK-HNF4α信号通路介导了AMPK的重要代谢效应。这项建议的总体目标是表征这一已提出的AMPK-HNF4pha信号通路的分子细节，并确定它对正常和糖尿病肝脏中基因表达和代谢的影响程度。此外，还将探讨AMPK介导的HNF4α磷酸化在二甲双胍和脂联素的肝脏效应中的作用。这些研究的结果将使我们更清楚地了解HNF4pha和AMPK之间的功能关系，并更全面地了解这两种重要蛋白质在肝脏中发挥的生理作用。

DESCRIPTION (provided by applicant): AMP activated protein kinase (AMPK) is the central component of a signaling system that functions to maintain cellular energy balance in response to stresses that deplete intracellular ATP. It is often referred to as a "metabolic master switch" because of the central role that it plays in the maintenance of metabolic homeostasis. AMPK activity has a strong influence on the regulation of whole body glucose metabolism and it may also play a role in the development of type-2 diabetes. It has recently been reported that some of the antidiabetic activities of the drug metformin and the hormone adiponectin may be mediated by activation of AMPK in the liver, suggesting a potential link between AMPK and hepatic glucose metabolism. We have recently demonstrated that the transcription factor HNF4alpha, a well-characterized regulator of metabolic gene expression in the liver, is inhibited by AMPK mediated phosphorylation on serine-304. HNF4alpha is known to play an important role in the expression of liver genes involved in regulating hepatic glucose production, a key contributor to normal and diabetic whole body glucose homeostasis. The central hypothesis of the work proposed here is that an AMPK-HNF4alpha signaling pathway in the liver mediates important metabolic effects of AMPK. The overall goals of this proposal are to characterize the molecular details of this proposed AMPK-HNF4alpha signaling pathway and to determine the extent to which it influences gene expression and metabolism in normal and diabetic liver. In addition, the possibility that AMPK mediated phosphorylation of HNF4alpha contributes to the hepatic effects of metformin and adiponectin will be explored. Results from these studies will provide a clearer understanding of the functional relationship between HNF4alpha and AMPK and a more complete picture of the physiological role that these two important proteins play in the liver.