School of Life Science, Handong Global University, Pohang, Kyungbuk 791-708, Republic of Korea.
Eur J Pharmacol. 2011 Dec 15;672(1-3):38-44. doi: 10.1016/j.ejphar.2011.09.172. Epub 2011 Sep 29.
Stearoyl-CoA desaturase1 (SCD1) whole body deficiency protects mice from diet-induced obesity. However the specific mechanism of how SCD1 deficiency protects mice from obesity is not clear yet. To understand the tissue-specific role of SCD1 in energy homeostasis, we investigated the responses of adipocytes, hepatocytes and myotubes to SCD1 inhibition. 3T3-L1 adipocytes treated with a SCD1 inhibitor had decreased expression of lipogenic genes including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and sterol-regulatory element binding protein 1c (SREBP1c) while the expression of fatty acid oxidative genes including carnitine palmitoyltransferase 1 (CPT1), uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α) remained unaltered. In mouse primary hepatocytes, treatment with the inhibitor reduced the expression of FAS, ACC, and SREBP1c but increased the expression of fatty acid oxidative genes including acyl-CoA oxidase (AOX), CPT1, and PGC1-α. In addition, inhibitor-treated C2C12 myotubes showed decrease in ACC and FAS expression and increase in expression of CPT1, AOX and PGC1-α. AMP-activated protein kinase (AMPK) is known to regulate cellular metabolism in response to available energy and AMPK activation is associated with enhancement of fatty acid oxidation and suppression of lipogenesis. In all tested cell models, AMPK phosphorylation was increased significantly when SCD1 was inhibited. Taken together, our results indicate that inhibition of SCD1 activity has beneficial lipid metabolic effects of decreased lipogenesis and/or increased fatty acid oxidation, which is at least in part due to an increase of AMPK activation.
硬脂酰辅酶 A 去饱和酶 1（SCD1）全身缺乏可保护小鼠免受饮食诱导的肥胖。然而，SCD1 缺乏如何保护小鼠免受肥胖的确切机制尚不清楚。为了了解 SCD1 在能量平衡中的组织特异性作用，我们研究了脂肪细胞、肝细胞和肌管对 SCD1 抑制的反应。用 SCD1 抑制剂处理的 3T3-L1 脂肪细胞中，包括脂肪酸合酶（FAS）、乙酰辅酶 A 羧化酶（ACC）和固醇调节元件结合蛋白 1c（SREBP1c）在内的脂肪生成基因的表达降低，而包括肉碱棕榈酰基转移酶 1（CPT1）、解偶联蛋白 2（UCP2）和过氧化物酶体增殖物激活受体γ共激活因子 1-α（PGC1-α）在内的脂肪酸氧化基因的表达保持不变。在小鼠原代肝细胞中，抑制剂处理降低了 FAS、ACC 和 SREBP1c 的表达，但增加了包括酰基辅酶 A 氧化酶（AOX）、CPT1 和 PGC1-α在内的脂肪酸氧化基因的表达。此外，抑制剂处理的 C2C12 肌管中 ACC 和 FAS 的表达减少，CPT1、AOX 和 PGC1-α 的表达增加。AMP 激活的蛋白激酶（AMPK）已知可根据可用能量调节细胞代谢，AMPK 的激活与增强脂肪酸氧化和抑制脂肪生成有关。在所有测试的细胞模型中，SCD1 被抑制时 AMPK 磷酸化显著增加。总之，我们的结果表明，抑制 SCD1 活性具有有益的脂质代谢作用，可减少脂肪生成和/或增加脂肪酸氧化，这至少部分归因于 AMPK 激活的增加。
