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

Suhara Tomohiro; Hishiki Takako; Kasahara MasatakaHayakawa NoriyoOyaizu TomokoNakanishi TsuyoshiKubo AkikoMorisaki HiroshiKaelin William G. Jr.Suematsu MakotoMinamishima Yoji Andrew

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

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

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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 hyper-lacticacidemia. 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 C-13-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from C-13-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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第37期|11642-11647|共6页
作者
Suhara Tomohiro; Hishiki Takako; Kasahara MasatakaHayakawa NoriyoOyaizu TomokoNakanishi TsuyoshiKubo AkikoMorisaki HiroshiKaelin William G. Jr.Suematsu MakotoMinamishima Yoji Andrew;
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作者单位

Keio Univ, Sch Med, Dept Biochem, Tokyo 1608582, Japan;

Keio Univ, Sch Med, Dept Anesthesiol, Tokyo 1608582, Japan;

Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
hypoxic response; PHD inhibitor; hyperlactatemia; gluconeogenesis; sepsis;

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

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