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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症（脂毒性）的主要原因。这一观点被大多数研究者所接受。然而，细胞内机制仍不清楚。因此，我们分析如下：1.幼年内脏脂肪变性（JVS）小鼠，我们在1991年报道，作为一种动物模型的原发性肉毒碱缺乏症。由于JVS小鼠具有缺陷的肉毒碱转运体（octn 2），并且细胞内肉毒碱水平保持低水平，长链酰基辅酶A被认为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小鼠胰岛体积较小。HE染色显示胰高血糖素含量保持不变，胰多肽含量下降。有些细胞保存了胰岛素的数量，但有些没有。(2)在25 μ M生理浓度的血清游离肉毒碱水平下，JVS小鼠心肌细胞的肉毒碱转运活性比正常对照组降低约20%。JVS小鼠心脏中游离肉毒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是对照组的11倍。为了解脂肪酸对胰岛β细胞功能的影响机制，将胰岛素瘤细胞株INS-1与棕榈酸共同孵育。棕榈酸引起三酰甘油的积累和表达速率（磷酸化Akt/Akt）增加。此外，还观察到NFk β信号转导的激活。因此，长链脂肪酸引起的代谢紊乱部分是由Akt磷酸化和NF κ β信号转导激活引起的.糖尿病大鼠心肌组织中Ca^<2+>含量明显升高，T_3可抑制心肌组织中Ca^<2+>含量的升高。