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（脂毒性）的一个重要原因，但其细胞内机制仍不清楚。1。我们于 1991 年报道，作为原发性肉碱缺乏症的动物模型，因为 JVS 小鼠肉碱转运蛋白 (octn 2) 有缺陷，细胞内肉碱水平仍然存在。低长链酰基辅酶A被认为积聚在胰岛细胞或心肌细胞中，因此我们对胰岛和心脏进行了分析。(1)通过HE染色，胰高血糖素的含量保持不变。 (2)JVS小鼠培养的肌细胞中肉碱转运活性比正常对照降低了约20%。 JVS小鼠心脏中的25μM游离肉碱水平约为正常对照的1-2%，在这种情况下，2-脱氧葡萄糖的摄取率比对照高11倍。 .2.为了了解脂肪酸对β细胞功能的毒性机制，将胰岛素瘤细胞系INS-1与棕榈酸酯一起孵育导致三酰甘油的积累和表达率（磷酸化）。 Akt/Akt) 增加，并且还观察到 NFk β 信号转导的激活，因此表明长链脂肪酸引起的代谢紊乱部分是由磷酸化的 Akt 和激活的 NFk β 信号转导引起的。糖尿病心脏表现出较高的Ca^2+含量并且被T_3抑制。