Department of Physiology of Ontogenesis, Biology Research Institute, Karazin Kharkov National University, Ukraine.
Biochemistry (Mosc). 2012 Feb;77(2):180-6. doi: 10.1134/S0006297912020095.
Ceramides are a novel class of biologically active molecules involved in the regulation of different signaling pathways. Ceramide is involved in regulation of the phospholipase D (PLD) activity and development of cell resistance to insulin. In this work, we have studied age-related features of insulin regulation of PLD activity and glucose metabolism in intact cells and modeled their resistance to insulin by exogenous ceramide and palmitic acid. Contents of ceramides and of free fatty acids (FFA) are found to increase with age, as well as on incubation of liver cells of young rats in the presence of the ceramide precursor palmitic acid. Under these conditions, the ability of insulin to activate PLD, the cell uptake of glucose, and glycogen synthesis sharply decreased. On incubation of hepatocytes of young animals in the presence of exogenous C2-ceramide, the contents of endogenous ceramides increased but not the contents of FFAs and of neutral lipids. These events were accompanied by suppression of the insulin-induced production of phosphatidylethanol (a result of ethanol transphosphatidylation by PLD), glucose uptake, and glycogen synthesis. Incubation of insulin-resistant liver cells of young rats and also of hepatocytes of old rats in the presence of myriocin (an inhibitor of the de novo synthesis of ceramide) was associated with a decrease in ceramide content in the cells and an increase in the cell sensitivity to insulin. The findings indicate an important role of ceramide in disturbance of insulin signaling due to inhibition of the PLD-dependent link in the liver cells of old animals.
神经酰胺是一类新型的生物活性分子，参与调节不同的信号通路。神经酰胺参与调节磷酯酶 D（PLD）的活性和细胞对胰岛素的抵抗性的发育。在这项工作中，我们研究了与年龄相关的胰岛素调节完整细胞中 PLD 活性和葡萄糖代谢的特征，并通过外源性神经酰胺和棕榈酸模拟其对胰岛素的抵抗性。结果发现，神经酰胺和游离脂肪酸（FFA）的含量随着年龄的增长而增加，而且在年轻大鼠的肝细胞在神经酰胺前体棕榈酸存在的情况下孵育时也是如此。在这些条件下，胰岛素激活 PLD、细胞摄取葡萄糖和糖原合成的能力急剧下降。在年轻动物的肝细胞存在外源性 C2-神经酰胺的情况下孵育时，内源性神经酰胺的含量增加，但 FFA 和中性脂质的含量没有增加。这些事件伴随着胰岛素诱导的磷脂酰乙醇产生的抑制（PLD 介导的乙醇转磷酸化的结果）、葡萄糖摄取和糖原合成的抑制。在存在霉菌素（神经酰胺从头合成的抑制剂）的情况下，年轻大鼠的胰岛素抵抗性肝细胞和老年大鼠的肝细胞孵育时，细胞中神经酰胺的含量降低，细胞对胰岛素的敏感性增加。这些发现表明，神经酰胺在老年动物肝细胞中通过抑制 PLD 依赖性途径干扰胰岛素信号转导中起着重要作用。
