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

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A Correction to this article was published on 20 May 2019

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Abstract

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.

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Change history

  • 20 May 2019

    Abstract

    The original version of this article unfortunately contained a mistake in the article title.

Abbreviations

AMPK:

AMP-activated protein kinase

DMEM:

Dulbecco’s modified Eagle’s medium

DPBS:

Dulbecco’s phosphate buffered saline

ER:

Endoplasmic reticulum

GLUT4:

Glucose transporter type 4

IP:

Immunoprecipitation

LDH:

Lactate dehydrogenase

NAD+ :

Nicotinamide adenine dinucleotide

NMN:

Nicotinamide mononucleotide

NAMPT:

Nicotinamide phosphoribosyltransferase

OCR:

Oxygen consumption rate

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PHGDH:

Phosphoglycerate dehydrogenase

PKM2:

Pyruvate kinase M2

qRT-PCR:

Quantitative real-time polymerase chain reaction

SIRT1:

Silent information regulator 1

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Funding

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.

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Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    Woo-Cheol Sim, Dong Gwang Kim, Wonseok Lee, Hyungtai Sim, You-Jin Choi & Byung-Hoon Lee

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  1. Woo-Cheol Sim
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  2. Dong Gwang Kim
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Sim, WC., Kim, D.G., Lee, W. et al. Activation of SIRT1 by l-serine increases fatty acid oxidation and reverses insulin resistance in C2C12 myotubes (l-serine activates SIRT1 in C2C12 myotubes). Cell Biol Toxicol 35, 457–470 (2019). https://doi.org/10.1007/s10565-019-09463-x

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