Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-α transgenic mice
Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-α transgenic mice
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DOI：
10.1152/ajpheart.00852.2002
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发表时间：
2003-07-01
影响因子：
4.8
通讯作者：
Lopaschuk, GD
中科院分区：
文献类型：
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作者：
Hopkins, TA;Sugden, MC;Lopaschuk, GD
丙酮酸脱氢酶复合物 (PDC) 是心脏中葡萄糖氧化的速率限制。终产物反馈对 PDC 的抑制和丙酮酸脱氢酶激酶 (PDK) 的磷酸化协同作用，抑制 PDC 活性。由于转录调节因子过氧化物酶体增殖物激活受体 (PPAR)-α 会增加某些组织中 PDK 的表达，因此我们研究了 PPAR-α 在过度表达 PPAR-α 的小鼠（MHC-PPAR-α 小鼠）心脏中调节葡萄糖氧化的作用。与野生型同窝小鼠相比，MHC-PPARα 小鼠离体工作心脏的葡萄糖氧化率降低（干重分别为 428 +/- 113 和 771 +/- 63 nmol.g(-1).min(-1)），同时脂肪酸氧化也相应增加。然而，尽管 MHC-PPAR-α 小鼠中 PDK 亚型 PDK1 的表达增加，但 MHC-PPAR-α 和野生型动物之间的 PDC 活性没有差异。禁食 48 小时（增加 PPAR-α 表达）或用 PPAR-α 激动剂 WY-14,643 治疗小鼠 1 周后，MHC-PPARα 和野生型小鼠心脏中的葡萄糖氧化率均降低。尽管如此，两个动物组的 PDC 活性均未改变。总而言之，这些数据表明，心脏中的葡萄糖氧化速率可以显着改变，而与 PDK 磷酸化和 PDK 对 PDC 的抑制无关。它还表明，PPAR-α 激活主要通过减少丙酮酸通过 PDC 的通量来减少心脏中的葡萄糖氧化，这是由于脂肪酸氧化反应产物而不是 PDC 复合物的磷酸化状态对 PDC 的负反馈。
The pyruvate dehydrogenase enzyme complex (PDC) is rate limiting for glucose oxidation in the heart. Inhibition of PDC by end-product feedback and phosphorylation by pyruvate dehydrogenase kinase (PDK) operate in concert to inhibit PDC activity. Because the transcriptional regulator peroxisome proliferator-activated receptor (PPAR)-alpha increases PDK expression in some tissues, we examined what role PPAR-alpha has in regulating glucose oxidation in hearts from mice overexpressing PPAR-alpha (MHC-PPAR-alpha mice). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPARalpha mice compared with wild-type littermates (428 +/- 113 vs. 771 +/- 63 nmol.g dry weight(-1).min(-1), respectively), which was accompanied by a parallel increase in fatty acid oxidation. However, there was no difference in PDC activity between MHC-PPAR-alpha and wild-type animals, even though the expression of the PDK isoform PDK1 was increased in MHC-PPAR-alpha mice. Glucose oxidation rates in both MHC-PPARalpha and wild-type mouse hearts were decreased after 48-h fasting (which increases PPAR-alpha expression) or by treatment of mice with the PPAR-alpha agonist WY-14,643 for 1 wk. Despite this, PDC activity in both animal groups was not altered. Taken together, these data suggest that glucose oxidation rates in the heart can be dramatically altered independent of PDK phosphorylation and inhibition of PDC by PDK. It also suggests that PPAR-alpha activation decreases glucose oxidation in hearts mainly by decreasing the flux of pyruvate through PDC due to negative feedback of PDC by fatty acid oxidation reaction products rather than by the phosphorylated state of the PDC complex.