Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP +/NADPH ratio

M. Itsumi, S. Inoue, A. J. Elia, K. Murakami, M. Sasaki, Evan Lind, D. Brenner, I. S. Harris, I. I C Chio, S. Afzal, R. A. Cairns, D. W. Cescon, A. R. Elford, J. Ye, P. A. Lang, W. Y. Li, A. Wakeham, G. S. Duncan, J. Haight, A. You-Ten & 4 others B. Snow, K. Yamamoto, P. S. Ohashi, T. W. Mak

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP +/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP +/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.

Original languageEnglish (US)
Pages (from-to)1837-1848
Number of pages12
JournalCell Death and Differentiation
Volume22
Issue number11
DOIs
StatePublished - Apr 17 2015
Externally publishedYes

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Isocitrate Dehydrogenase
NADP
Endotoxins
Hepatocytes
Oxidative Stress
Lipopolysaccharides
Liver
Reactive Oxygen Species
Septic Shock
Serum
Knockout Mice
DNA Damage
Interleukin-6
Tumor Necrosis Factor-alpha
Antioxidants

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP +/NADPH ratio. / Itsumi, M.; Inoue, S.; Elia, A. J.; Murakami, K.; Sasaki, M.; Lind, Evan; Brenner, D.; Harris, I. S.; Chio, I. I C; Afzal, S.; Cairns, R. A.; Cescon, D. W.; Elford, A. R.; Ye, J.; Lang, P. A.; Li, W. Y.; Wakeham, A.; Duncan, G. S.; Haight, J.; You-Ten, A.; Snow, B.; Yamamoto, K.; Ohashi, P. S.; Mak, T. W.

In: Cell Death and Differentiation, Vol. 22, No. 11, 17.04.2015, p. 1837-1848.

Research output: Contribution to journalArticle

Itsumi, M, Inoue, S, Elia, AJ, Murakami, K, Sasaki, M, Lind, E, Brenner, D, Harris, IS, Chio, IIC, Afzal, S, Cairns, RA, Cescon, DW, Elford, AR, Ye, J, Lang, PA, Li, WY, Wakeham, A, Duncan, GS, Haight, J, You-Ten, A, Snow, B, Yamamoto, K, Ohashi, PS & Mak, TW 2015, 'Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP +/NADPH ratio', Cell Death and Differentiation, vol. 22, no. 11, pp. 1837-1848. https://doi.org/10.1038/cdd.2015.38
Itsumi, M. ; Inoue, S. ; Elia, A. J. ; Murakami, K. ; Sasaki, M. ; Lind, Evan ; Brenner, D. ; Harris, I. S. ; Chio, I. I C ; Afzal, S. ; Cairns, R. A. ; Cescon, D. W. ; Elford, A. R. ; Ye, J. ; Lang, P. A. ; Li, W. Y. ; Wakeham, A. ; Duncan, G. S. ; Haight, J. ; You-Ten, A. ; Snow, B. ; Yamamoto, K. ; Ohashi, P. S. ; Mak, T. W. / Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP +/NADPH ratio. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 11. pp. 1837-1848.
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abstract = "Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP +/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP +/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.",
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T1 - Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP +/NADPH ratio

AU - Itsumi, M.

AU - Inoue, S.

AU - Elia, A. J.

AU - Murakami, K.

AU - Sasaki, M.

AU - Lind, Evan

AU - Brenner, D.

AU - Harris, I. S.

AU - Chio, I. I C

AU - Afzal, S.

AU - Cairns, R. A.

AU - Cescon, D. W.

AU - Elford, A. R.

AU - Ye, J.

AU - Lang, P. A.

AU - Li, W. Y.

AU - Wakeham, A.

AU - Duncan, G. S.

AU - Haight, J.

AU - You-Ten, A.

AU - Snow, B.

AU - Yamamoto, K.

AU - Ohashi, P. S.

AU - Mak, T. W.

PY - 2015/4/17

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N2 - Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP +/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP +/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.

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