Hormonal Regulation of Enzyme Levels in Mammalian Tissue

说明(由申请人提供)胞浆形式的磷酸烯醇式丙酮酸羧激酶(PEPCK-C)对能量代谢至关重要；它会导致出生后2天内死亡，肝脏中脂质大量堆积，并出现严重的低血糖。PEPCK-C基因在多种哺乳动物组织中表达，最重要的是肝脏、脂肪组织和肾皮质。PEPCK-C在这些组织中的作用对于该组织中能量代谢的正常功能至关重要。在肝脏中，PEPCK-C基因被转录，以响应动物营养状态的变化，并参与肝脏的糖异生和甘油异生。肝脏中PEPCK-C基因的转录主要受高血糖素(通过cAMP起作用)和糖皮质激素(刺激转录)和胰岛素(抑制转录)的控制。在脂肪组织中，PEPCK-C参与调节脂肪酸再酯化(甘油生成)的速率；该组织中基因的转录受儿茶酚胺、糖皮质激素和胰岛素的控制。PEPCK-C是一个单拷贝基因，因此转录的差异调控是转录因子和控制基因表达的共激活因子的组合的结果；一些是组织特有的，而另一些是所有三个组织共享的。这项研究的目的是描述参与这一过程的因素，并开发一种将特定组织中PEPCK-C基因转录的激素调节与该酶在动物中的生理作用相结合的模型。我们将集中在肝脏中的胰高血糖素、糖皮质激素和胰岛素以及脂肪组织中的糖皮质激素和胰岛素对转录的调节，并将开发一个模型来解释这些激素在这两种组织中的作用。这项研究对糖尿病和肥胖症具有特殊的意义，因为PEPCK-C是控制肝脏葡萄糖输出和脂肪组织中甘油三酯沉积的关键酶。

DESCRIPTION (provided by applicant) The cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) is critical for energy metabolism; it ablation results in death within 2 days after birth, with massive accumulation of lipid in the liver and severe hypoglycemia. The gene for PEPCK-C is expressed in a variety of mammalian tissue, most importantly the liver, adipose tissue and kidney cortex. The role of PEPCK-C in each of these tissues is vital for the proper functioning of energy metabolism in that tissue. In the liver, the gene for PEPCK-C is transcribed in response to alterations in the nutritional status of the animal and is involved in both hepatic gluconeogenesis and glyceroneogenesis. PEPCK-C gene transcription in the liver is mainly controlled by glucagon (acting via cAMP) and glucocorticoids, which stimulate transcription and by insulin, which inhibits transcription. In adipose tissue, PEPCK-C is involved in regulating the rate of fatty acid re-esterification (glyceroneogenesis); the transcription of the gene in that tissue is controlled and by catecholamines, glucocorticoids and insulin. PEPCK-C is a single copy gene, so that the differential regulation of transcription is the result of a combination of transcription factors and co-activators that control gene expression; some are tissue-specific, while others are shared by all three tissues. The goal of this research is to delineate the factors that are involved in this process and to develop a model that integrates the hormonal regulation of PEPCK-C gene transcription in specific tissues with the physiological role of the enzyme in animals. We will concentrate on the regulation of transcription by glucagon, glucocorticoids and insulin in the liver and by glucocorticoids and insulin in the adipose tissue and will develop a model to explain the action of these hormones in the two tissues. This research has special significance to diabetes and obesity, since PEPCK-C is a critical enzyme in both the control of hepatic glucose output and triglyceride deposition in adipose tissue.