Is lipotoxicity caused by the intracellular accumulation ofacyl CoA ?

长链脂肪酸被认为是高血糖(脂毒性)的重要原因。这一概念被大多数调查人员接受。然而，其细胞内机制尚不清楚。因此，我们进行了如下分析。我们1991年报道的幼年内脏脂肪变性(JVS)小鼠是一种原发性肉碱缺乏的动物模型。由于JVS小鼠存在肉碱转运体(Octn2)缺陷，且细胞内肉碱水平较低，故推测长链酰辅酶A在胰岛细胞或心肌细胞中积聚。因此，我们对胰岛和心脏进行了分析。(1)JVS小鼠胰岛体积较小。苏木精-伊红染色后，胰升糖素含量维持不变，而胰多肽含量下降。(2)25μM游离肉碱浓度为血清生理浓度时，JVS小鼠心肌细胞的肉碱转运活性较正常对照组下降约20%。JVS小鼠心脏中的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是对照组的11倍。为了解脂肪酸对β细胞功能的毒性机制，用棕榈酸酯与胰岛素瘤细胞株INS-1孵育。棕榈酸引起三酰甘油的积累，并且表达速率(磷酸化Akt/Akt)增加。此外，还观察到NFKβ信号转导通路的激活。因此，提示长链脂肪酸引起的代谢紊乱部分是由于AKT的磷酸化和NFKβ信号转导的激活所致。糖尿病心脏表现出较高的Ca~(2+)和Gt~(2+)含量，且可被T_3抑制。

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.