Is lipotoxicity caused by the intracellular accumulation ofacyl CoA ?

脂毒性是由细胞内酰基辅酶A的积累引起的吗？

基本信息

批准号：
12470229
负责人：
KUWAJIMA Masamichi
金额：
$ 8.13万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470229/
关键词：
carnitine carintine transporter insulin JVS mouse octn2 glucagon 2-DG uptake fatty acid octn2 膵β細胞長鎖脂肪酸高血糖脂肪毒性膵ラ氏島

项目摘要

Long chain fatty acid is thought to be a strong cause of hyperglycemia (Lipotoxicity). This concept is accepted by most investigators. However, the intracellular mechanism remains unclear. Therefore, we analyzed as follows.1. Juvenile visceral steatosis (JVS) mouse, which we reported in 1991, serves as an animal model of primary carnitine deficiency. Because JVS mouse has a defective carnitine transporter (octn 2) and intracellular carnitine level remains low, long chain acyl-CoA is supposed to be accumulated in pancreatic islet cells or cardiac myocytes. Therefore we analyzed the islets and heart.(1) Size of islet of JVS mouse was small. By HE staining, content of glucagon was maintained, however content of pancreatic polypeptide was decreased. Some cells conserved the amount of insulin, but some did not.(2) Carnitine transport activity in cultured myocyte of JVS mouse was decreased by about 20 percent of normal control at 25 μ M free carnitine level which is the physiological concentration in serum. Free carnitine level in JVS mouse heart is about 1-2 percent of normal control. In such a case, uptake rate of 2-deoxyglucose was eleven times higher than that of control.2. To know the mechanism the fatty acid toxicity on β -cell function, insulinoma cell line INS-1 was incubated with palmitate. Palmitate caused the accumulation of triacylglycerol and expression rate (phosphorylated Akt/Akt) was increased. Also, activation of NFk β signal transduction was observed. Therefore, it is suggested that metabolic derangement by long-chain fatty acid was, in part, caused by phosphorylated Akt and activated NFk β signal transduction.3. Diabetic heart showed a higher Ca^<2+> content and it was inhibited by T_3.

长链脂肪酸被认为是高血糖（脂肪毒性）的强大原因。这个概念被大多数研究人员接受。但是，细胞内机制尚不清楚。因此，我们分析如下1。我们在1991年报告的少年内脏脂肪变性（JVS）小鼠是原发性肉碱缺乏的动物模型。由于JVS小鼠的肉碱转运蛋白（Octn 2）和细胞内肉碱水平保持较低，因此预计长链酰基辅酶A将在胰岛细胞或心肌细胞中积累。因此，我们分析了胰岛和心脏。（1）JVS小鼠胰岛的大小很小。通过染色，保持胰高血糖素的含量，但是胰多肽的含量降低了。一些细胞保留了胰岛素的含量，但有些则没有。（2）JVS小鼠2的培养肌细胞中的肉碱转运活性。要了解β细胞功能上的脂肪酸毒性，将胰岛素瘤细胞系INS -1与棕榈酸酯一起孵育。棕榈酸酯引起三酰基甘油的积累，表达速率（磷酸化的AKT/AKT）增加了。同样，观察到NFKβ信号转导的激活。因此，建议长链脂肪酸的代谢进化部分是由磷酸化的AKT和激活的NFKβ信号转导引起的。3。糖尿病心脏显示出更高的Ca^<2+>含量，并被T_3抑制。