title: Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Itsumi
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Elia
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: E F
authors.initials: EF
authors.lastname: Lind
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg.
authors.forename: D
authors.initials: D
authors.lastname: Brenner
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: I S
authors.initials: IS
authors.lastname: Harris
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: I I C
authors.initials: II
authors.lastname: Chio
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5G 2C1, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Afzal
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: R A
authors.initials: RA
authors.lastname: Cairns
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: D W
authors.initials: DW
authors.lastname: Cescon
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: A R
authors.initials: AR
authors.lastname: Elford
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ye
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.|Department of Molecular Medicine II, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.
authors.forename: P A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: W Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: G S
authors.initials: GS
authors.lastname: Duncan
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Haight
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: A
authors.initials: A
authors.lastname: You-Ten
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Snow
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5G 2C1, Canada.
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Immunology, University of Toronto, Toronto, ON M5G 2C1, Canada.
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology*; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004731:Endotoxins; D009249:NADP; D007521:Isocitrate Dehydrogenase