Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C 2 C 12 myogenic cells
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Online ISSN 1976-3786 Print ISSN 0253-6269
RESEARCH ARTICLE
Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C2C12 myogenic cells Mei-Chen Lo1,2 • Jia-Yin Chen3 • Yung-Ting Kuo1,4 • Wei-Lu Chen2 Horng-Mo Lee5 • Shyang-Guang Wang3,6
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Received: 26 September 2018 / Accepted: 15 April 2019 The Pharmaceutical Society of Korea 2019
Abstract 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 C2C12 myogenic cells. Treatment of C2C12 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
& Shyang-Guang Wang [email protected] 1
Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
2
Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan
3
Institute of Medical Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
4
Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
5
Department of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
6
Present Address: Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
(ATGL), decreased the amount of intracellular oil droplets, and significantly increased b-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. Keywords Camptothecin SIRT1 AMP-activated protein kinase Adipose triglyceride lipase
Introduction Sirtuin 1 (SIRT1) plays an important role in mediating longevity and health benefits associated with caloric restriction (Hoshino et al. 2018). SIRT1 regulates the expression of numerous genes and metabolic pathways, such as insulin secretion, whole-body glucose homeostasis and insulin sensitivity, fatty acid b-oxidation, and lipid
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