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Non-esterified fatty acids activate the ROS–p38–p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro

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Abstract

A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-l-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS–p38–p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.

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Abbreviations

BSA:

Bovine serum albumin

CAT:

Catalase

GLU:

Glucose

GSH:

Glutathione

GSSG:

Glutathione disulfide

GSH-Px:

Glutathione peroxidase

Keap1:

Kelch-like ECH-associated protein 1

MDA:

Malonaldehyde

Mdm2:

Mouse double minute 2 homolog

NAC:

N-acetyl-l-cysteine

NEB:

Negative energy balance

NEFA:

Non-esterified fatty acids

Nrf2:

Nuclear factor erythroid 2-related factor2

p38MAPK:

p38 mitogen-activated protein kinases

p53:

Tumor protein p53

RET:

Reverse electron transfer

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TAC:

Total antioxidant capacity

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Acknowledgments

This work was supported by the National High Technology R&D Program (No. 2013AA102806), the National Key Technology R&D Program (No. 2012BAD12B03), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, No. IRT1248), the National Natural Science Foundation of China (Beijing, China; Grant No. 30871897, 30972224, 31072178, 31172372, 31272621, 31360630, 31372478 and 31372494), the Program for New Century Excellent Talents in University (NCET-11-0199).

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Authors and Affiliations

  1. Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi’an Road, Changchun, 130062, Jilin, China

    Yuxiang Song, Xinwei Li, Yu Li, Xiaoxia Shi, Hongyan Ding, Xiaobing Li, Guowen Liu & Zhe Wang

  2. Laboratory of Microbiology and Immunology, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China

    Na Li

  3. College of Animal Science and Technology, Jilin Agricultural Science and Technology College, Jilin, Jilin, China

    Yuhang Zhang

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  1. Yuxiang Song
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  2. Xinwei Li
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  3. Yu Li
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  4. Na Li
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  8. Xiaobing Li
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  10. Zhe Wang
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Corresponding authors

Correspondence to Xiaobing Li or Guowen Liu.

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Yuxiang Song and Xinwei Li contributed equally to this study.

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Song, Y., Li, X., Li, Y. et al. Non-esterified fatty acids activate the ROS–p38–p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro. Apoptosis 19, 984–997 (2014). https://doi.org/10.1007/s10495-014-0982-3

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