Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3-L1 adipocytes via the endothelial NO synthase-cGMP-protein kinase G signalling pathway
Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3-L1 adipocytes via the endothelial NO synthase-cGMP-protein kinase G signalling pathway
复制标题
硫辛酰胺或硫辛酸通过内皮NO合酶-cGMP-蛋白激酶G信号通路刺激3T3-L1脂肪细胞中的线粒体生物发生
DOI：
10.1111/j.1476-5381.2010.01134.x
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发表时间：
2011-03-01
影响因子：
7.3
通讯作者：
Liu, Jiankang
中科院分区：
文献类型：
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作者：
Shen, Weili;Hao, Jiejie;Liu, Jiankang
背景和目的由于线粒体丢失导致的代谢功能障碍在糖尿病中起重要作用，抗糖尿病药物刺激线粒体生物发生可改善线粒体功能。在寻找线粒体生物发生的有效刺激剂的过程中，我们研究了硫辛酰胺和α-硫辛酸（LA）在脂肪细胞中的作用和机制。实验方法用硫辛酰胺或LA处理分化的3T3-L1脂肪细胞。检查了线粒体生物发生和可能的信号传导途径。关键结果将 3T3-L1 细胞暴露于硫辛酰胺或 LA 24 小时，每个细胞的线粒体数量和质量增加。这种治疗还增加了线粒体 DNA 拷贝数、蛋白质水平和参与线粒体生物合成的转录因子的表达，包括 PGC-1 α、线粒体转录因子 A 和核呼吸因子 1。硫辛酰胺在 1 和 10 μ mol 中心点 L-1 浓度下产生这些作用，而 LA 在 100 μ mol 中心点 L-1 浓度下最有效。在 10 μmol 中心点 L-1 处，硫辛酰胺（而非 LA）刺激 PPAR-γ、PPAR-α 和 CPT-1 α 的 mRNA 表达。硫辛酰胺的效力比 LA 强 10-100 倍。硫辛酰胺剂量依赖性地刺激内皮一氧化氮合酶 (eNOS) 的表达和 cGMP 的形成。 eNOS 的敲低（带有小干扰 RNA）可阻止硫辛酰胺诱导的线粒体生物发生，而可溶性鸟苷酸环化酶抑制剂 ODQ 和蛋白激酶 G (PKG) 抑制剂 KT5823 也可阻断这种生物发生。因此，硫辛酰胺对线粒体生物发生的刺激涉及通过 eNOS-cGMP-PKG 途径的信号传导。结论和意义我们的数据表明，硫辛酰胺是脂肪细胞中线粒体生物发生的有效刺激剂，并且可能在肥胖和糖尿病方面具有潜在的治疗应用。
BACKGROUND AND PURPOSEMetabolic dysfunction due to loss of mitochondria plays an important role in diabetes, and stimulation of mitochondrial biogenesis by anti-diabetic drugs improves mitochondrial function. In a search for potent stimulators of mitochondrial biogenesis, we examined the effects and mechanisms of lipoamide and alpha-lipoic acid (LA) in adipocytes.EXPERIMENTAL APPROACHDifferentiated 3T3-L1 adipocytes were treated with lipoamide or LA. Mitochondrial biogenesis and possible signalling pathways were examined.KEY RESULTSExposure of 3T3-L1 cells to lipoamide or LA for 24 h increased the number and mitochondrial mass per cell. Such treatment also increased mitochondrial DNA copy number, protein levels and expression of transcription factors involved in mitochondrial biogenesis, including PGC-1 alpha, mitochondrial transcription factor A and nuclear respiratory factor 1. Lipoamide produced these effects at concentrations of 1 and 10 mu mol center dot L-1, whereas LA was most effective at 100 mu mol center dot L-1. At 10 mu mol center dot L-1, lipoamide, but not LA, stimulated mRNA expressions of PPAR-gamma, PPAR-alpha and CPT-1 alpha. The potency of lipoamide was 10-100-fold greater than that of LA. Lipoamide dose-dependently stimulated expression of endothelial nitric oxide synthase (eNOS) and formation of cGMP. Knockdown of eNOS (with small interfering RNA) prevented lipoamide-induced mitochondrial biogenesis, which was also blocked by the soluble guanylate cyclase inhibitor, ODQ and the protein kinase G (PKG) inhibitor, KT5823. Thus, stimulation of mitochondrial biogenesis by lipoamide involved signalling via the eNOS-cGMP-PKG pathway.CONCLUSIONS AND IMPLICATIONSOur data suggest that lipoamide is a potent stimulator of mitochondrial biogenesis in adipocyte, and may have potential therapeutic application in obesity and diabetes.