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 Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
JournalArchives of Pharmacal Research
DOIs
Publication statusE-pub ahead of print - Apr 24 2019

Keywords

  • AMP-activated protein kinase
  • Adipose triglyceride lipase
  • Camptothecin
  • SIRT1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Organic Chemistry

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