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

• Published in: Cell death and differentiation Vol. 22; no. 11; pp. 1837 - 1845
• Main Authors: Itsumi, M, Inoue, S, Elia, A J, Murakami, K, Sasaki, M, Lind, E F, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2015; Nature Publishing Group
• Subjects: 631/250/1933; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cells, Cultured; Endotoxins - pharmacology; Flow Cytometry; Hepatocytes - drug effects; Hepatocytes - enzymology; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Life Sciences; Mice; Mice, Knockout; NADP - metabolism; Original Paper; Oxidative Stress - drug effects; Oxidative Stress - genetics; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.38

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.