CARNITINE PALMITOYLTRANSFERASE AND FATTY ACID METABOLISM

线粒体肉碱棕榈酰基转移酶系统CPT(由 CPT-1和CPT-II以及转位酶)在 哺乳动物组织中脂肪酸代谢的调节。它有 作为潜在的药理作用场所而受到越来越多的关注 对高血糖状态的干预，现在被认为是一个基因座 对于人类的突变，有些会带来严重的后果。解开 关于这种复杂的运输机制的细节在最近几年中进展迅速 好几年了。例如，所有三种CPT同工酶的氨基酸序列 目前已知的是CPTII和迄今为止由丙二酰辅酶A调节的两个 大鼠和人的CPT-I(L)活体和(M)肌)的亚型； 所有三个CPT基因的染色体定位；心脏同时表达这两种基因 CPT I型；在大鼠和人类白色脂肪中以M变异为主 细胞和发育中的大鼠精子；CPT系统出现 是胰岛β细胞功能的重要元素。 调查人员现在希望澄清首都的结构 CPT-1基因，它们是如何被调控的，抑制物如何与 CPT1蛋白，为什么L和M-CPT1蛋白表现出如此大的差异 性质，对各种代谢过程的影响具有组织特异性 CPT-1基因敲除，以及CPT-1缺乏的遗传基础。 还需要研究的问题是，消脂作用是否 新发现的荷尔蒙瘦素涉及CPT 1的变化 在选定的身体中通过这一步骤的活动和/或脂肪酸流动 网站。最后，调查人员应开始探讨 CPT-1在精子发育和功能中的作用以及CPT-1抑制剂如何 在这个层面上的影响。 拟议中的实验将回答许多重要的问题 扩大CPT在完整生物体中的调节作用领域。的 尤其重要的是，所获得的信息应该提供更大的 脂肪酸代谢异常在病因学中的作用 β细胞功能障碍和胰岛素抵抗的特征 肥胖和II型糖尿病综合征，疾病正在蔓延 美国的流行病比例。

The mitochondrial carnitine palmitoyltransferase system CPT (composed of CPT 1 and CPTII and a translocase) plays a pivotal role in the regulation of fatty acid metabolism in mammalian tissues. It has received increasing attention as a potential site for pharmacologic interventions in hyperglycemic states and is now recognized as a locus for human mutation, some with serious consequences. Unraveling the details of this complex transport mechanism has moved rapidly in recent years. For example, the amino acids sequences of all three CPT isozymes are now known i.e. CPTII and the two so far malonyl-COA-regulated isoforms of CPT-I (L) live and (M) muscle) from both rat and human; the chromosome location of all three CPT genes; that heart expresses both type of CPT I; that the M variant dominates in rat and human white fat cells as well as in developing rat sperm; and that CPT system appears to be an important element in pancreatic beta-cell function. The investigators now wish to elucidate the structures of the capital CPT 1 genes, how they are regulated, how inhibitors interact with the CPT 1 proteins, why proteins L and M- CPT 1 display such very different properties, the impact on various metabolic processes of tissue-specific CPT 1 knock out, and the genetic basis of CPT 1 deficiency. Also to be studied is the question of whether the fat dissipating action of the newly discovered hormone, leptin, involves alterations in CPT 1 activity and/or fatty acid flux through this step in selected body sites. Finally, the investigators shall begin to explore the role of CPT 1 in sperm development and function, and how CPT 1 inhibitors might impact at this level. The proposed experiments will answer many important questions in the expanding realm of CPT regulatory effects in the intact organism. Of particular importance, the information gained should provide greater insight into the role of abnormal fatty acid metabolism in the etiology of beta cell dysfunction and insulin resistance that characterize obesity and Type II diabetes syndromes, disorders that are reaching epidemic proportions in the United States.