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Archives of Pharmacal Research

, Volume 42, Issue 8, pp 672–683 | Cite as

Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C2C12 myogenic cells

  • Mei-Chen Lo
  • Jia-Yin Chen
  • Yung-Ting Kuo
  • Wei-Lu Chen
  • Horng-Mo Lee
  • Shyang-Guang WangEmail author
Research Article
  • 186 Downloads

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 (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.

Keywords

Camptothecin SIRT1 AMP-activated protein kinase Adipose triglyceride lipase 

Notes

Acknowledgements

This work was supported by research grants from Central Taiwan University of Science and Technology (Grant No. PTH10026 to S.-G.W.) and the  Ministry of Science and Technology of Taiwan (Grant Nos. MOST-104-2320-B-038-064 and MOST-101-2320-B-166-001-MY3 to H.-M.L.).

Compliance with ethical standard

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Shuang Ho HospitalTaipei Medical UniversityTaipeiTaiwan
  2. 2.Department of NursingCentral Taiwan University of Science and TechnologyTaichungTaiwan
  3. 3.Institute of Medical BiotechnologyCentral Taiwan University of Science and TechnologyTaichungTaiwan
  4. 4.Department of Pediatrics, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
  5. 5.Department of Medical Laboratory Science and Biotechnology, College of Medical Science and TechnologyTaipei Medical UniversityTaipeiTaiwan
  6. 6.Department of Medical Laboratory Science and BiotechnologyCentral Taiwan University of Science and TechnologyTaichungTaiwan

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