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Article

The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model

  • Authors:
    • Yusuke Ishida
    • Hidetoshi Fujita
    • Satoko Aratani
    • Miyuki Chijiiwa
    • Noboru Taniguchi
    • Maho Yokota
    • Yukihiko Ogihara
    • Naomi Uoshima
    • Fumiaki Nagashima
    • Hiroyuki Uchino
    • Toshihiro Nakajima
  • View Affiliations / Copyright

    Affiliations: Department of Anesthesiology, Tokyo Medical University Hospital, Tokyo 160‑0023, Japan, Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan, Department of Medicine of Sensory and Motor Organs, Division of Orthopedic Surgery, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889‑1692, Japan
  • Pages: 2467-2475
    |
    Published online on: June 15, 2018
       https://doi.org/10.3892/mmr.2018.9175
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Abstract

Sepsis‑associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP‑induced septic mice. Notably, KYN was not detected in CLP‑induced septic Syvn1‑deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1‑deficient mice compared to that in wild‑type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose‑dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF‑E2‑related factor 2 and peroxisome proliferator‑activated receptor coactivator 1β, which are targets of Syvn1‑induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP‑induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.
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Copy and paste a formatted citation
Spandidos Publications style
Ishida Y, Fujita H, Aratani S, Chijiiwa M, Taniguchi N, Yokota M, Ogihara Y, Uoshima N, Nagashima F, Uchino H, Uchino H, et al: The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model. Mol Med Rep 18: 2467-2475, 2018.
APA
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M. ... Nakajima, T. (2018). The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model. Molecular Medicine Reports, 18, 2467-2475. https://doi.org/10.3892/mmr.2018.9175
MLA
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M., Ogihara, Y., Uoshima, N., Nagashima, F., Uchino, H., Nakajima, T."The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model". Molecular Medicine Reports 18.2 (2018): 2467-2475.
Chicago
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M., Ogihara, Y., Uoshima, N., Nagashima, F., Uchino, H., Nakajima, T."The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model". Molecular Medicine Reports 18, no. 2 (2018): 2467-2475. https://doi.org/10.3892/mmr.2018.9175
Copy and paste a formatted citation
x
Spandidos Publications style
Ishida Y, Fujita H, Aratani S, Chijiiwa M, Taniguchi N, Yokota M, Ogihara Y, Uoshima N, Nagashima F, Uchino H, Uchino H, et al: The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model. Mol Med Rep 18: 2467-2475, 2018.
APA
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M. ... Nakajima, T. (2018). The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model. Molecular Medicine Reports, 18, 2467-2475. https://doi.org/10.3892/mmr.2018.9175
MLA
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M., Ogihara, Y., Uoshima, N., Nagashima, F., Uchino, H., Nakajima, T."The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model". Molecular Medicine Reports 18.2 (2018): 2467-2475.
Chicago
Ishida, Y., Fujita, H., Aratani, S., Chijiiwa, M., Taniguchi, N., Yokota, M., Ogihara, Y., Uoshima, N., Nagashima, F., Uchino, H., Nakajima, T."The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model". Molecular Medicine Reports 18, no. 2 (2018): 2467-2475. https://doi.org/10.3892/mmr.2018.9175
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