Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Diabetologia. 2012 Jun;55(6):1824-35. doi: 10.1007/s00125-012-2530-4. Epub 2012 Mar 30.
AIMS/HYPOTHESIS: Sirtuin 1 (SIRT1) is a longevity-associated protein, which regulates energy metabolism and lifespan in response to nutrient deprivation. It has been proposed to be a therapeutic target for obesity and metabolic syndrome. We investigated whether α-lipoic acid (ALA) exerts a lipid-lowering effect through regulation of SIRT1 activation and production in C(2)C(12) myotubes.
ALA-stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), adipose triacylglycerol lipase (ATGL) and fatty acid synthase (FAS) production, as well as intracellular triacylglycerol accumulation and fatty acid β-oxidation were analysed in the absence or presence of a SIRT1 inhibitor (nicotinamide), SIRT1 small interfering (si) RNA and an AMPK inhibitor (compound C) in C(2)C(12) myotubes. Mice with streptozotocin/nicotinamide-induced diabetes and db/db mice fed on a high-fat diet were used to study the ALA-mediated lipid-lowering effects in vivo.
ALA increased the NAD(+)/NADH ratio to enhance SIRT1 activity and production in C(2)C(12) myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate β-oxidation and decreased intracellular triacylglycerol accumulation in C(2)C(12) myotubes. In cells treated with nicotinamide or transfected with SIRT1 siRNA, ALA-mediated AMPK/ACC phosphorylation, intracellular triacylglycerol accumulation and palmitate β-oxidation were reduced, suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein production in C(2)C(12) myotubes. Oral administration of ALA in diabetic mice fed on a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content.
CONCLUSIONS/INTERPRETATION: ALA activates both SIRT1 and AMPK, which leads to lipid-lowering effects in vitro and in vivo. These findings suggest that ALA may have beneficial effects in the treatment of dyslipidaemia and obesity.
目的/假设：Sirtuin 1（SIRT1）是一种与长寿相关的蛋白质，它可以响应营养缺乏调节能量代谢和寿命。它被提议作为肥胖和代谢综合征的治疗靶点。我们研究了α-硫辛酸（ALA）是否通过调节 C(2)C(12)肌管中的 SIRT1 激活和产生来发挥降低血脂的作用。
在不存在或存在 SIRT1 抑制剂（烟酰胺）、SIRT1 小干扰（si）RNA 和 AMPK 抑制剂（化合物 C）的情况下，分析 ALA 刺激 AMP 激活的蛋白激酶（AMPK）、乙酰辅酶 A 羧化酶（ACC）、脂肪三酰甘油脂肪酶（ATGL）和脂肪酸合酶（FAS）的产生，以及 C(2)C(12)肌管内三酰甘油的积累和脂肪酸的β-氧化。使用链脲佐菌素/烟酰胺诱导的糖尿病小鼠和高脂肪饮食喂养的 db/db 小鼠研究 ALA 介导的体内降脂作用。
ALA 增加 NAD(+)/NADH 比值，以增强 C(2)C(12)肌管中的 SIRT1 活性和产生。随后，ALA 增加 AMPK 和 ACC 的磷酸化，导致棕榈酸的β-氧化增加和 C(2)C(12)肌管内三酰甘油积累减少。在用烟酰胺处理的细胞或转染 SIRT1 siRNA 的细胞中，ALA 介导的 AMPK/ACC 磷酸化、细胞内三酰甘油积累和棕榈酸的β-氧化减少，表明 SIRT1 是 AMPK 的上游调节剂。ALA 增加了 C(2)C(12)肌管中的 ATGL 并抑制了 FAS 蛋白的产生。在高脂肪饮食喂养的糖尿病小鼠和 db/db 小鼠中口服 ALA 可显著降低体重和内脏脂肪含量。
结论/解释：ALA 激活 SIRT1 和 AMPK，在体外和体内均具有降低血脂的作用。这些发现表明，ALA 可能对治疗血脂异常和肥胖具有有益作用。
