Hopkins Teresa A, Sugden Mary C, Holness Mark J, Kozak Ray, Dyck Jason R B, Lopaschuk Gary D
Departments of Pharmacology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H270-6. doi: 10.1152/ajpheart.00852.2002. Epub 2003 Mar 27.
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-PPAR-alpha mice compared with wild-type littermates (428 +/- 113 vs. 771 +/- 63 nmol x g dry weight-1x 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-PPAR-alpha 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.
丙酮酸脱氢酶复合体（PDC）是心脏中葡萄糖氧化的限速酶。终产物反馈对PDC的抑制作用以及丙酮酸脱氢酶激酶（PDK）介导的磷酸化作用共同抑制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可增加某些组织中PDK的表达，因此我们研究了PPAR-α在过表达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-PPAR-α小鼠离体工作心脏的葡萄糖氧化速率降低（分别为428±113和771±63 nmol·g干重⁻¹·min⁻¹），同时脂肪酸氧化相应增加。然而，尽管MHC-PPAR-α小鼠中PDK亚型PDK1的表达增加，但MHC-PPAR-α小鼠与野生型动物之间的PDC活性并无差异。禁食48小时（可增加PPAR-α表达）或用PPAR-α激动剂WY-14,643处理小鼠1周后，MHC-PPAR-α和野生型小鼠心脏的葡萄糖氧化速率均降低。尽管如此，两个动物组的PDC活性均未改变。综上所述，这些数据表明，心脏中的葡萄糖氧化速率可在不依赖于PDK磷酸化和PDK对PDC抑制的情况下发生显著改变。这也表明，PPAR-α激活主要通过脂肪酸氧化反应产物对PDC的负反馈，而非PDC复合体的磷酸化状态，减少丙酮酸通过PDC的通量，从而降低心脏中的葡萄糖氧化。
