GlaxoSmithKline, Les Ulis Cedex, France.
Eur J Pharmacol. 2009 Sep 15;618(1-3):28-36. doi: 10.1016/j.ejphar.2009.07.004. Epub 2009 Jul 17.
Stearoyl-CoA Desaturase 1 (SCD1) is a central enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. SCD1 is an emerging target in obesity and insulin resistance due to the improved metabolic profile obtained when the enzyme is genetically inactivated. Here, we have investigated if the pharmacological inhibition of SCD1 could elicit the same profile. We have identified a small molecule, GSK993 and characterized it as a potent and orally available SCD1 inhibitor. In Zucker(fa/fa) rats, GSK993 exerted a marked reduction in hepatic lipids as well as a significant improvement of glucose tolerance. Furthermore, in a diet-induced insulin resistant rat model, GSK993 induced a very strong reduction in Triton-induced hepatic Very Low Density Lipoprotein-Triglyceride production. In addition, following a hyperinsulinemic-euglycemic clamp in GSK993-treated animals, we observed an improvement in the whole body insulin sensitivity as reflected by an increase in the glucose infusion rate. Taken together, these findings demonstrate that the pharmacological inhibition of SCD1 translates into improved lipid and glucose metabolic profiles and raises the interest of SCD1 inhibitors as potential new drugs for the treatment of insulin resistance.
硬脂酰辅酶 A 去饱和酶 1（SCD1）是一种催化饱和脂肪酸生成单不饱和脂肪酸的关键酶。由于酶基因失活后代谢谱得到改善，SCD1 成为肥胖和胰岛素抵抗的新兴靶点。在此，我们研究了 SCD1 的药理学抑制是否能产生相同的作用。我们发现了一种小分子 GSK993，并将其鉴定为一种有效的、口服可用的 SCD1 抑制剂。在 Zucker（fa/fa）大鼠中，GSK993 显著降低了肝脏脂质，同时显著改善了葡萄糖耐量。此外，在饮食诱导的胰岛素抵抗大鼠模型中，GSK993 可强烈抑制 Triton 诱导的肝极低密度脂蛋白-甘油三酯生成。此外，在 GSK993 处理的动物进行高胰岛素-正葡萄糖钳夹后，我们观察到全身胰岛素敏感性得到改善，葡萄糖输注率增加。综上所述，这些发现表明 SCD1 的药理学抑制可转化为改善的脂质和葡萄糖代谢谱，并提高 SCD1 抑制剂作为治疗胰岛素抵抗的潜在新药的兴趣。
