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

TitleIdh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP+/NADPH ratio
Authors
Issue Date2015
Citation
Cell Death and Differentiation, 2015, v. 22, n. 11, p. 1837-1845 How to Cite?
AbstractIsocitrate 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.
Persistent Identifierhttp://hdl.handle.net/10722/292905
ISSN
2023 Impact Factor: 13.7
2023 SCImago Journal Rankings: 4.102
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorItsumi, M.-
dc.contributor.authorInoue, S.-
dc.contributor.authorElia, A. J.-
dc.contributor.authorMurakami, K.-
dc.contributor.authorSasaki, M.-
dc.contributor.authorLind, E. F.-
dc.contributor.authorBrenner, D.-
dc.contributor.authorHarris, I. S.-
dc.contributor.authorChio, I. I.C.-
dc.contributor.authorAfzal, S.-
dc.contributor.authorCairns, R. A.-
dc.contributor.authorCescon, D. W.-
dc.contributor.authorElford, A. R.-
dc.contributor.authorYe, J.-
dc.contributor.authorLang, P. A.-
dc.contributor.authorLi, W. Y.-
dc.contributor.authorWakeham, A.-
dc.contributor.authorDuncan, G. S.-
dc.contributor.authorHaight, J.-
dc.contributor.authorYou-Ten, A.-
dc.contributor.authorSnow, B.-
dc.contributor.authorYamamoto, K.-
dc.contributor.authorOhashi, P. S.-
dc.contributor.authorMak, T. W.-
dc.date.accessioned2020-11-17T14:57:28Z-
dc.date.available2020-11-17T14:57:28Z-
dc.date.issued2015-
dc.identifier.citationCell Death and Differentiation, 2015, v. 22, n. 11, p. 1837-1845-
dc.identifier.issn1350-9047-
dc.identifier.urihttp://hdl.handle.net/10722/292905-
dc.description.abstractIsocitrate 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.-
dc.languageeng-
dc.relation.ispartofCell Death and Differentiation-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleIdh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP+/NADPH ratio-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/cdd.2015.38-
dc.identifier.pmid25882048-
dc.identifier.pmcidPMC4648331-
dc.identifier.scopuseid_2-s2.0-84943200604-
dc.identifier.volume22-
dc.identifier.issue11-
dc.identifier.spage1837-
dc.identifier.epage1845-
dc.identifier.eissn1476-5403-
dc.identifier.isiWOS:000362438500011-
dc.identifier.issnl1350-9047-

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