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

Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11642-7. doi: 10.1073/pnas.1515872112. Epub 2015 Aug 31.

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 (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.

Keywords: PHD inhibitor; gluconeogenesis; hyperlactatemia; hypoxic response; sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / metabolism*
  • Animals
  • Blood Gas Analysis
  • Blood Glucose / metabolism
  • Genotype
  • Hepatocytes / metabolism
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Lactates / metabolism
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxygen / metabolism*
  • Physical Conditioning, Animal
  • Sepsis / metabolism

Substances

  • Blood Glucose
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lactates
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Oxygen