Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle

Tomohiro Suhara, Takako Hishiki, Masataka Kasahara, Noriyo Hayakawa, Tomoko Toramaru, Tsuyoshi Nakanishi, Akiko Kubo, Hiroshi Morisaki, William G. Kaelin, Makoto Suematsu, Yoji Andrew Minamishima

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19 Citations (Scopus)

Abstract

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 <sup>13</sup>C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from <sup>13</sup>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.

Original languageEnglish
Pages (from-to)11642-11647
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number37
DOIs
Publication statusPublished - 2015 Sep 15

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Keywords

  • Gluconeogenesis
  • Hyperlactatemia
  • Hypoxic response
  • PHD inhibitor
  • Sepsis

ASJC Scopus subject areas

  • General

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