REGULATION OF GLUCOSE AND FATTY ACID METABOLISM

这个建议的主旨是阐明调节和相互作用 肝脏和非肝脏组织中的碳水化合物和脂质代谢， 尤其是心脏和骨骼肌。 上一次赠款的进展情况 人们对葡萄糖稳态的传统概念产生了怀疑。 在 此外，丙二酰辅酶A在脂肪代谢中的调节作用的有趣方面， 酸代谢已经被发现 因此，两大类 调查将会展开。 第一个涉及到对 启动分解代谢转化为 再喂食禁食动物时的合成代谢。 三个主要问题 将提出：（1）是什么控制葡萄糖-6-磷酸流入糖原或 空腹血糖及其逆转 (2)是什么决定了 糖原是直接或间接（通过乳酸）从葡萄糖形成的？ （三） 什么控制果糖-2，6-二磷酸水平在肝脏后 重新进食 第二个系列的实验解决了监管问题， 丙二酰辅酶A与肉毒碱棕榈酰转移酶I相互作用 I），脂肪酸氧化和生酮的限速酶。 再次，三个主要问题将被问到：（1）丙二酰辅酶A是一种 非肝组织脂肪酸代谢的生理调节剂？ （二） 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 正常的燃料代谢和疾病状态下的紊乱- 尤其是不受控制的糖尿病。

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.