Activation of SIRT1 by l-serine increases fatty acid oxidation and reverses insulin resistance in C2C12 myotubes (l-serine activates SIRT1 in C2C12 myotubes)

  • Woo-Cheol Sim
  • Dong Gwang Kim
  • Wonseok Lee
  • Hyungtai Sim
  • You-Jin Choi
  • Byung-Hoon LeeEmail author
Original Article


Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, and the function is linked to cellular metabolism including mitochondrial biogenesis. Hepatic l-serine concentration is decreased significantly in fatty liver disease. We reported that the supplementation of the amino acid ameliorated the alcoholic fatty liver by enhancing l-serine-dependent homocysteine metabolism. In this study, we hypothesized that the metabolic production of NAD+ from l-serine and thus activation of SIRT1 contribute to the action of l-serine. To this end, we evaluated the effects of l-serine on SIRT1 activity and mitochondria biogenesis in C2C12 myotubes. l-Serine increased intracellular NAD+ content and led to the activation of SIRT1 as determined by p53 luciferase assay and western blot analysis of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) acetylation. l-Serine treatment increased the expression of the genes associated with mitochondrial biogenesis and enhanced mitochondrial mass and function. In addition, l-serine reversed cellular insulin resistance determined by insulin-induced phosphorylation of Akt and GLUT4 expression and membrane translocation. l-Serine-induced mitochondrial gene expression, fatty acid oxidation, and insulin sensitization were mediated by enhanced SIRT1 activity, which was verified by selective SIRT1 inhibitor (Ex-527) and siRNA directed to SIRT1. l-Serine effect on cellular NAD+ level is dependent on the l-serine metabolism to pyruvate that is subsequently converted to lactate by lactate dehydrogenase. In summary, these data suggest that l-serine increases cellular NAD+ level and thus SIRT1 activity in C2C12 myotubes.


Insulin resistance l-Serine Mitochondrial biogenesis Nicotinamide adenine dinucleotide (NAD+Silent information regulator 1 (SIRT1) 



AMP-activated protein kinase


Dulbecco’s modified Eagle’s medium


Dulbecco’s phosphate buffered saline


Endoplasmic reticulum


Glucose transporter type 4




Lactate dehydrogenase


Nicotinamide adenine dinucleotide


Nicotinamide mononucleotide


Nicotinamide phosphoribosyltransferase


Oxygen consumption rate


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


Phosphoglycerate dehydrogenase


Pyruvate kinase M2


Quantitative real-time polymerase chain reaction


Silent information regulator 1


Funding information

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2017R1A2B4003179) and a grant (16173MFDS009) from Ministry of Food and Drug Safety in 2017.

Supplementary material

10565_2019_9463_MOESM1_ESM.docx (15 kb)
Supplemental Table 1 (DOCX 15 kb)
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Supplemental Figure 1 (PPTX 213 kb)
10565_2019_9463_MOESM3_ESM.pptx (126 kb)
Supplemental Figure 2 (PPTX 126 kb)
10565_2019_9463_MOESM4_ESM.pptx (296 kb)
Supplemental Figure 3 (PPTX 295 kb)


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Woo-Cheol Sim
    • 1
  • Dong Gwang Kim
    • 1
  • Wonseok Lee
    • 1
  • Hyungtai Sim
    • 1
  • You-Jin Choi
    • 1
  • Byung-Hoon Lee
    • 1
    Email author
  1. 1.College of Pharmacy and Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulRepublic of Korea

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