Suhara Tomohiro, Hishiki Takako, Kasahara Masataka, Hayakawa Noriyo, Oyaizu Tomoko, Nakanishi Tsuyoshi, Kubo Akiko, Morisaki Hiroshi, Kaelin William G, Suematsu Makoto, Minamishima Yoji Andrew
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Anesthesiology, Keio University School of Medicine, Tokyo 160-8582, Japan;
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;
Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11642-7. doi: 10.1073/pnas.1515872112. Epub 2015 Aug 31.
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.
脯氨酰羟化酶2（PHD2）的缺失会激活缺氧诱导因子依赖性缺氧反应，包括无氧糖酵解，这会导致大量乳酸从细胞释放到循环中。正如预期的那样，我们发现Phd2基因敲除的小鼠胚胎成纤维细胞（MEF）比野生型MEF产生更多的乳酸，然而小鼠体内PHD2的系统性失活并未导致高乳酸血症。这一意外发现使我们推测，肝脏中激活的缺氧反应增强了科里循环（Cori cycle），即肌肉和肝脏之间的乳酸 - 葡萄糖碳循环系统，从而降低了循环中的乳酸水平。与这一假设一致，在跑步机运动或乳酸耐量试验后测量的Phd2肝脏特异性敲除（Phd2-LKO）小鼠的血乳酸水平显著低于对照小鼠。体内（13）C标记的乳酸掺入试验表明，Phd2-LKO小鼠的肝脏从（13）C标记的乳酸中产生的葡萄糖比对照小鼠显著更多，这表明肝脏中PHD2的阻断通过激活乳酸糖异生来改善乳酸酸中毒。Phd2-LKO小鼠对注射致死剂量乳酸诱导的乳酸酸中毒具有抗性，存活时间显著延长。此外，口服PHD抑制剂可提高内毒素休克小鼠模型的存活率。这些数据表明，PHD2是治疗乳酸酸中毒的潜在新型药物靶点，乳酸酸中毒是一些重症患者中观察到的严重且往往致命的并发症。
