CARNITINE PALMITOYLTRANSFERASE AND FATTY ACID METABOLISM

线粒体肉毒碱棕榈酰转移酶系统CPT（由 CPT 1和CPTII和转位酶）在细胞凋亡中起着关键作用。 哺乳动物组织中脂肪酸代谢的调节。 它有 作为潜在的药理学研究中心， 高血糖状态的干预，现在被认为是一个位点， 人类基因突变，有些会带来严重的后果 Unraveling the 近年来，这种复杂的运输机制的细节迅速发展， 年 例如，所有三种CPT同工酶的氨基酸序列 即CPTII和迄今为止的两种丙二酰辅酶A调节的 CPT-I（L）肝脏和（M）肌肉）的同种型; 所有三个CPT基因的染色体定位;心脏表达两者 CPT I型; M变体在大鼠和人白色脂肪中占主导地位 细胞以及发育中的大鼠精子; CPT系统出现 是胰腺β细胞功能的重要组成部分。 调查人员现在希望阐明首都的结构 CPT 1基因，它们是如何调节的，抑制剂如何与 CPT 1蛋白质，为什么蛋白质L和M-CPT 1显示如此不同 性质，对组织特异性的各种代谢过程的影响 CPT 1基因敲除，CPT 1缺陷的遗传基础. 还需要研究的问题是， 新发现的激素瘦素，涉及CPT 1的改变 活性和/或脂肪酸通量通过该步骤在选定的身体 网站. 最后，调查人员应开始探索以下方面的作用： 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的范围。 的 特别重要的是，所获得的信息应提供更多 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， 肥胖和II型糖尿病综合征， 在美国的流行比例。

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.