Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle.
Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan;
Tomohiro
T
Suhara
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Translational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan;
Takako
T
Hishiki
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Pharmacology, Tokyo Dental College, Tokyo 101-0061, Japan;
Masataka
M
Kasahara
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Translational Research Center, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan;
Noriyo
N
Hayakawa
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan;
Tomoko
T
Oyaizu
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; MS Business Unit, Shimadzu Corporation, Kyoto 604-8511, Japan;
Tsuyoshi
T
Nakanishi
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan;
Akiko
A
Kubo
Department of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan;
Hiroshi
H
Morisaki
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215; Howard Hughes Medical Institute, Chevy Chase, MD 20815 william_kaelin@dfci.harvard.edu gasbiology@keio.jp yoji_andrew_minamishima@keio.jp.
William G
WG
Kaelin
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; william_kaelin@dfci.harvard.edu gasbiology@keio.jp yoji_andrew_minamishima@keio.jp.
Makoto
M
Suematsu
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Core Research for Evolutional Science and Technology, Tokyo 160-8582, Japan; william_kaelin@dfci.harvard.edu gasbiology@keio.jp yoji_andrew_minamishima@keio.jp.
Yoji Andrew
http://orcid.org/0000-0001-7995-9318
YA
Minamishima
D000140:Acidosis, Lactic / Q000378:metabolism*; D000818:Animals; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000378:metabolism; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D018805:Sepsis / Q000378:metabolism
D001786:Blood Glucose; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen
PHD inhibitor; gluconeogenesis; hyperlactatemia; hypoxic response; sepsis