PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.
PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.
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DOI：
10.1161/circresaha.117.311456
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发表时间：
2017-12-08
影响因子：
20.1
通讯作者：
Arany Z
中科院分区：
文献类型：
--
作者：
Liu LX;Rowe GC;Yang S;Li J;Damilano F;Chan MC;Lu W;Jang C;Wada S;Morley M;Hesse M;Fleischmann BK;Rabinowitz JD;Das S;Rosenzweig A;Arany Z
怀孕深刻地改变了母亲的生理。妊娠期间心脏肥大，但其代谢适应尚不清楚。目的：确定妊娠期间心脏底物使用的潜在机制。我们在这里使用13C-葡萄糖、13C-乳酸和13C-脂肪酸的示踪分析来表明，妊娠晚期小鼠的心脏增加了脂肪酸的摄取和氧化进入三羧酸(TCA)循环，而减少了葡萄糖和乳酸的氧化。线粒体的数量、形态和功能似乎没有改变。胰岛素信号看起来完好无损，主要的脂肪酸和葡萄糖转运蛋白CD36和GLUT4的丰度和定位也没有变化。相反，我们发现孕激素孕酮诱导心肌细胞中的丙酮酸脱氢酶激酶(PDK)-4，而妊娠晚期PDK4水平的升高导致丙酮酸脱氢酶(PDH)和丙酮酸进入TCA循环的抑制。阻断PDK4可以逆转妊娠晚期心脏的代谢变化。综上所述，这些数据表明，妊娠晚期的激素环境在PDH水平而不是在胰岛素信号水平上促进心脏代谢重塑。
Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. To determine the mechanisms underlying cardiac substrate use during pregnancy. We use here 13C-glucose, 13C-lactate, and 13C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.