Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan.
Arch Pharm Res. 2019 Aug;42(8):672-683. doi: 10.1007/s12272-019-01155-8. Epub 2019 Apr 24.
Caloric restriction activates sirtuin 1 (SIRT1) and induces a variety of metabolic effects that are beneficial for preventing age-related disease. The present study screened a commercially available used drug library to develop small molecule activators of SIRT1 as therapeutics for treatment of metabolic disorders. Using an in vitro fluorescence assay, the cancer therapeutic camptothecin increased SIRT1 enzymatic activity by 5.5-fold, indicating it to be a potent SIRT1 activator. Camptothecin also elevated the nicotinamide adenine dinucleotide (NAD)/NADH ratio and increased SIRT1 protein levels in differentiated CC myogenic cells. Treatment of CC myotubes with camptothecin increased phosphorylation of AMP-dependent kinase (AMPK) and acetyl-coenzyme A carboxylase, caused nuclear translocation and deacetylation of forkhead box O1 (FoxO1), increased transcription and protein expression of adipose triglyceride lipase (ATGL), decreased the amount of intracellular oil droplets, and significantly increased β-oxidation of fatty acids. These in vitro data were confirmed in vivo as camptothecin treatment of C57BL/6J mice reduced fat and plasma triglyceride levels. All of the above camptothecin-induced alterations were attenuated by the SIRT1-specific inhibitor nicotinamide and/or 6-[4-(2-piperidin-1-ylethoxy) phenyl]-3-pyridin-4-ylpyrazolo [1,5-a]pyrimidin (compound C). Thus, camptothecin activation of SIRT1 promotes lipid catabolism through AMPK/FoxO1/ATGL signaling.
热量限制激活了沉默调节蛋白 1（SIRT1），并诱导了多种有益于预防与年龄相关疾病的代谢效应。本研究筛选了市售的药物库，以开发 SIRT1 的小分子激活剂作为治疗代谢紊乱的药物。通过体外荧光测定法，癌症治疗药物喜树碱使 SIRT1 酶活性增加了 5.5 倍，表明其为一种有效的 SIRT1 激活剂。喜树碱还提高了烟酰胺腺嘌呤二核苷酸（NAD）/NADH 比值，并增加了分化的 CC 成肌细胞中的 SIRT1 蛋白水平。喜树碱处理 CC 肌管增加了 AMP 依赖的激酶（AMPK）和乙酰辅酶 A 羧化酶的磷酸化，导致叉头框 O1（FoxO1）的核易位和去乙酰化，脂肪甘油三酯脂肪酶（ATGL）的转录和蛋白表达增加，细胞内油滴减少，脂肪酸的β氧化显著增加。体内实验数据证实了这一点，因为喜树碱治疗 C57BL/6J 小鼠可降低脂肪和血浆甘油三酯水平。SIRT1 特异性抑制剂烟酰胺和/或 6-[4-(2-哌啶-1-基乙氧基)苯基]-3-吡啶-4-基吡唑并[1,5-a]嘧啶（化合物 C）可减弱喜树碱引起的所有上述变化。因此，喜树碱激活 SIRT1 通过 AMPK/FoxO1/ATGL 信号通路促进脂肪分解。
