REGULATION OF GLUCOSE AND FATTY ACID METABOLISM

这一建议的主旨是阐明监管和相互作用 肝脏和非肝脏组织中的碳水化合物和脂肪代谢， 尤其是心脏和骨骼肌。上一笔拨款的发展 这一时期使人们对传统的葡萄糖稳态概念产生了怀疑。在……里面 此外，丙二酰辅酶A在脂肪中的调节作用的有趣方面 酸的代谢已经显露无遗。因此，有两条大致的路线 将进行调查。第一个问题涉及到对 启动分解代谢转化为 当禁食的动物被重新喂养时，合成代谢。三个主要问题 将提出：(1)是什么控制了葡萄糖-6-磷酸流入糖原或 禁食中的血糖及其逆转？(2)是什么决定了 糖原是由葡萄糖直接或间接(通过乳酸)形成的？ 是什么控制了肝脏中2，6-二磷酸果糖的水平 重新进食？第二系列实验针对的是监管 丙二酰辅酶A与肉碱棕榈酰转移酶I(CPT)的相互作用 I)，脂肪酸氧化和酮类生成的限速酶。 我们将再次提出三个主要问题：(1)丙二酰辅酶A是 非肝组织中脂肪酸代谢的生理调节？(2) CPT I和CPT II是不同的酶吗？(3)丙二酰辅酶A如何抑制 CPT I？这些问题的答案对于理解 正常的燃料代谢及其在疾病状态下的紊乱- 尤其是未得到控制的糖尿病。

The thrust of this proposal is to elucidate the regulation and interaction of carbohydrate and lipid metabolism in the liver and non-hepatic tissues, especially heart and skeletal muscle. Developments over the last grant period have cast doubt on traditional concepts of glucose homeostasis. In addition, intriguing aspects of the regulatory role of malonyl-CoA in fatty acid metabolism have come to light. Accordingly, two broad lines of investigation will be carried out. The first involves a study of the regulatory events initiating the conversion of catabolic metabolism to anabolic metabolism when fasted animals are refed. Three main questions will be posed: (1) what controls glucose-6-phosphate flow into glycogen or plasma glucose in fasting and its reversal? (2) What dictates whether glycogen is formed directly or indirectly (via lactate) from glucose? (3) What controls fructose-2, 6-bisphosphate levels in the liver after refeeding? The second series of experiments addresses the regulatory interaction between malonyl-CoA and carnitine palmitoyl-transferase I (CPT I), the rate limiting enzyme for fatty acid oxidation and ketogenesis. Again, three major questions will be asked: (1) is malonyl-CoA a physiologic regulator of fatty acid metabolism in non-hepatic tissues? (2) Are CPT I and CPT II different enzymes? (3) How does malonyl-CoA inhibit CPT I? Answers to these questions are important for an understanding of normal fuel metabolism and its derangements in disease states - particularly uncontrolled diabetes.