Cytosolic carnitine acetyltransferase as a source of cytosolic acetyl-CoA: a possible mechanism for regulation of cardiac energy metabolism
Cytosolic carnitine acetyltransferase as a source of cytosolic acetyl-CoA: a possible mechanism for regulation of cardiac energy metabolism
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DOI：
10.1042/bcj20170823
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发表时间：
2018-03-15
影响因子：
4.1
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
--
作者：
Altamimi, Tariq R.;Thomas, Panakkezhum D.;Lopaschuk, Gary D.
肉毒碱乙酰转移酶（CrAT）在调节心脏能量代谢中的作用知之甚少。CrAT调节线粒体乙酰辅酶A/辅酶A（辅酶A）比率，从而调节丙酮酸脱氢酶活性和葡萄糖氧化。在这里，我们提出，心脏CrAT还提供了细胞溶质乙酰辅酶A的生产丙二酰辅酶A，一种有效的脂肪酸氧化抑制剂。我们发现，在小鼠心肌细胞胞质溶胶中，反向CrAT活性（RCrAT，产生乙酰辅酶A）高于肝脏，肝脏主要使用ATP-柠檬酸裂解酶产生胞质乙酰辅酶A用于脂肪生成。与肝脏相比，心脏对CoA的RCrAT K-m较低。此外，细胞溶质RCrAT占心脏组织中总活性的4.6 +/- 0.7%和H9 C2细胞中的12.7 +/- 0.2%，而高度纯化的心脏细胞溶质组分显示出显著的CrAT蛋白水平。为了研究CrAT和乙酰辅酶A羧化酶（ACC）之间的关系，ACC是催化乙酰辅酶A产生丙二酰辅酶A的胞浆酶，我们研究了ACC 2基因敲除小鼠心脏，与对照组相比，其显示CrAT蛋白水平和活性降低，棕榈酸氧化和乙酰辅酶A/辅酶A比值增加。相反，给小鼠喂高脂饮食10周增加了心脏CrAT蛋白水平和活性，与乙酰辅酶A/辅酶A比率降低和葡萄糖氧化有关。这些数据支持存在对CoA具有低K-m的胞质CrAT，有利于胞质乙酰CoA的形成，为经典ATP-柠檬酸裂解酶途径提供额外来源，并且CrAT与乙酰CoA/CoA比率之间存在反比关系，这在影响心脏能量代谢调节的条件下是明显的。
The role of carnitine acetyltransferase (CrAT) in regulating cardiac energy metabolism is poorly understood. CrAT modulates mitochondrial acetyl-CoA/CoA (coenzyme A) ratios, thus regulating pyruvate dehydrogenase activity and glucose oxidation. Here, we propose that cardiac CrAT also provides cytosolic acetyl-CoA for the production of malonyl-CoA, a potent inhibitor of fatty acid oxidation. We show that in the murine cardiomyocyte cytosol, reverse CrAT activity (RCrAT, producing acetyl-CoA) is higher compared with the liver, which primarily uses ATP-citrate lyase to produce cytosolic acetyl-CoA for lipogenesis. The heart displayed a lower RCrAT K-m for CoA compared with the liver. Furthermore, cytosolic RCrAT accounted for 4.6 +/- 0.7% of total activity in heart tissue and 12.7 +/- 0.2% in H9C2 cells, while highly purified heart cytosolic fractions showed significant CrAT protein levels. To investigate the relationship between CrAT and acetyl-CoA carboxylase (ACC), the cytosolic enzyme catalyzing malonyl-CoA production from acetyl-CoA, we studied ACC2-knockout mouse hearts which showed decreased CrAT protein levels and activity, associated with increased palmitate oxidation and acetyl-CoA/CoA ratio compared with controls. Conversely, feeding mice a high-fat diet for 10 weeks increased cardiac CrAT protein levels and activity, associated with a reduced acetyl-CoA/CoA ratio and glucose oxidation. These data support the presence of a cytosolic CrAT with a low K-m for CoA, favoring the formation of cytosolic acetyl-CoA, providing an additional source to the classical ATP-citrate lyase pathway, and that there is an inverse relation between CrAT and the ratio of acetyl-CoA/CoA as evident in conditions affecting the regulation of cardiac energy metabolism.