Campbell Fiona M, Kozak Ray, Wagner Alese, Altarejos Judith Y, Dyck Jason R B, Belke Darrell D, Severson David L, Kelly Daniel P, Lopaschuk Gary D
Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Biol Chem. 2002 Feb 8;277(6):4098-103. doi: 10.1074/jbc.M106054200. Epub 2001 Dec 4.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor transcription factor that has an important role in controlling cardiac metabolic gene expression. We determined whether mice lacking PPARalpha (PPARalpha (-/-) mice) have alterations in cardiac energy metabolism. Rates of palmitate oxidation were significantly decreased in isolated working hearts from PPARalpha (-/-) hearts compared with hearts from age-matched wild type mice (PPARalpha (+/+) mice), (62 +/- 12 versus 154 +/- 65 nmol/g dry weight/min, respectively, p < 0.05). This was compensated for by significant increases in the rates of glucose oxidation and glycolysis. The decreased fatty acid oxidation in PPARalpha (-/-) hearts was associated with increased levels of cardiac malonyl-CoA compared with PPARalpha (+/+) hearts (15.15 +/- 1.63 versus 7.37 +/- 1.31 nmol/g, dry weight, respectively, p < 0.05). Since malonyl-CoA is an important regulator of cardiac fatty acid oxidation, we also determined if the enzymes that control malonyl-CoA levels in the heart are under transcriptional control of PPARalpha. Expression of both mRNA and protein as well as the activity of malonyl-CoA decarboxylase, which degrades malonyl-CoA, were significantly decreased in the PPARalpha (-/-) hearts. In contrast, the expression and activity of acetyl-CoA carboxylase, which synthesizes malonyl-CoA and 5'-AMP-activated protein kinase, which regulates acetyl-CoA carboxylase, were not altered. Glucose transporter expression (GLUT1 and GLUT4) was not different between PPARalpha (-/-) and PPARalpha (+/+) hearts, suggesting that the increase in glycolysis and glucose oxidation in the PPARalpha null mice was not due to direct effects on glucose uptake but rather was occurring secondary to the decrease in fatty acid oxidation. This study demonstrates that PPARalpha is an important regulator of fatty acid oxidation in the heart and that this regulation of fatty acid oxidation may in part occur due to the transcriptional control of malonyl-CoA decarboxylase.
过氧化物酶体增殖物激活受体α（PPARα）是一种核受体转录因子，在控制心脏代谢基因表达方面发挥着重要作用。我们研究了缺乏PPARα的小鼠（PPARα（-/-）小鼠）的心脏能量代谢是否存在改变。与年龄匹配的野生型小鼠（PPARα（+/ +）小鼠）的心脏相比，PPARα（-/-）心脏的离体工作心脏中棕榈酸氧化速率显著降低（分别为62±12和154±65 nmol/g干重/分钟，p<0.05）。这通过葡萄糖氧化和糖酵解速率的显著增加得到了补偿。与PPARα（+/ +）心脏相比，PPARα（-/-）心脏中脂肪酸氧化的减少与心脏丙二酰辅酶A水平的增加有关（分别为15.15±1.63和7.37±1.31 nmol/g干重，p<0.05）。由于丙二酰辅酶A是心脏脂肪酸氧化的重要调节因子我们还确定了控制心脏中丙二酰辅酶A水平的酶是否受PPARα的转录控制。PPARα（-/-）心脏中降解丙二酰辅酶A的丙二酰辅酶A脱羧酶的mRNA和蛋白质表达以及活性均显著降低。相比之下，合成丙二酰辅酶A的乙酰辅酶A羧化酶和调节乙酰辅酶A羧化酶的5'-AMP激活蛋白激酶的表达和活性没有改变。PPARα（-/-）和PPARα（+/ +）心脏之间的葡萄糖转运蛋白表达（GLUT1和GLUT4）没有差异，这表明PPARα基因敲除小鼠中糖酵解和葡萄糖氧化的增加不是由于对葡萄糖摄取的直接影响，而是继发于脂肪酸氧化的减少。这项研究表明，PPARα是心脏脂肪酸氧化的重要调节因子，这种对脂肪酸氧化的调节可能部分是由于丙二酰辅酶A脱羧酶的转录控制。
