TY - JOUR
T1 - Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C2C12 myogenic cells
AU - Lo, Mei-Chen
AU - Chen, Jia-Yin
AU - Kuo, Yung-Ting
AU - Chen, Wei-Lu
AU - Lee, Horng-Mo
AU - Wang, Shyang-Guang
N1 - Funding Information:
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.).
Publisher Copyright:
© 2019, The Pharmaceutical Society of Korea.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - AMP-activated protein kinase
KW - Adipose triglyceride lipase
KW - Camptothecin
KW - SIRT1
UR - http://www.scopus.com/inward/record.url?scp=85064848380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064848380&partnerID=8YFLogxK
U2 - 10.1007/s12272-019-01155-8
DO - 10.1007/s12272-019-01155-8
M3 - Article
C2 - 31020545
SN - 0253-6269
VL - 42
SP - 672
EP - 683
JO - Archives of Pharmacal Research
JF - Archives of Pharmacal Research
IS - 8
ER -
