Babenko N A, Kharchenko V S
Department of Physiology of Ontogenesis, Institute of Biology, Kharkov Karazin National University, Kharkov, 61077, Ukraine.
Biochemistry (Mosc). 2015 Jan;80(1):104-12. doi: 10.1134/S0006297915010125.
Sphingolipids play an important role in the development of insulin resistance. Ceramides are the most potent inhibitors of insulin signal transduction. Ceramides are generated in response to stress stimuli and in old age. In this work, we studied the possible contribution of different pathways of sphingolipid metabolism in age-dependent insulin resistance development in liver cells. Inhibition of key enzymes of sphingolipid synthesis (serine palmitoyl transferase, ceramide synthase) and degradation (neutral and acidic SMases) by means of specific inhibitors (myriocin, fumonisin B1, imipramine, and GW4869) was followed with the reduction of ceramide level and partly improved insulin regulation of glucose metabolism in "old" hepatocytes. Imipramine and GW4869 decreased significantly the acidic and neutral SMase activities, respectively. Treatment of "old" cells with myriocin or fumonisin B1 reduced the elevated in old age ceramide and SM synthesis. Ceramide and SM levels and glucose metabolism regulation by insulin could be improved with concerted action of all tested inhibitors of sphingolipid turnover on hepatocytes. The data demonstrate that not only newly synthesized ceramide and SM but also neutral and acidic SMase-dependent ceramide accumulation plays an important role in development of age-dependent insulin resistance.
鞘脂在胰岛素抵抗的发展中起重要作用。神经酰胺是胰岛素信号转导的最有效抑制剂。神经酰胺是在应激刺激和老年时产生的。在这项工作中，我们研究了鞘脂代谢的不同途径在肝细胞年龄依赖性胰岛素抵抗发展中的可能作用。通过特异性抑制剂（myriocin、伏马菌素B1、丙咪嗪和GW4869）抑制鞘脂合成（丝氨酸棕榈酰转移酶、神经酰胺合酶）和降解（中性和酸性鞘磷脂酶）的关键酶，随后神经酰胺水平降低，“老年”肝细胞中胰岛素对葡萄糖代谢的调节部分得到改善。丙咪嗪和GW4869分别显著降低了酸性和中性鞘磷脂酶的活性。用myriocin或伏马菌素B1处理“老年”细胞可降低老年时升高的神经酰胺和鞘磷脂合成。通过对肝细胞鞘脂周转的所有测试抑制剂的协同作用，可以改善神经酰胺和鞘磷脂水平以及胰岛素对葡萄糖代谢的调节。数据表明，不仅新合成的神经酰胺和鞘磷脂，而且中性和酸性鞘磷脂酶依赖性神经酰胺积累在年龄依赖性胰岛素抵抗的发展中起重要作用。
