Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation
Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation
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DOI：
10.1042/bst20140094
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发表时间：
2014-08-01
影响因子：
3.9
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
--
作者：
Alrob, Osama Abo;Lopaschuk, Gary D.
CoA（辅酶A）及其衍生物在调节心脏能量代谢中具有关键作用。这包括作为能量代谢途径中的底物和产物的关键作用，以及作为心脏能量代谢的变构调节剂。此外，CoA 酯丙二酰辅酶 A 在调节脂肪酸氧化方面具有重要作用，继发于抑制 CPT（肉碱棕榈酰转移酶）1，CPT 是参与线粒体脂肪酸摄取的关键酶。 ACC（乙酰辅酶A羧化酶）对丙二酰辅酶A合成的改变和MCD（丙二酰辅酶A脱羧酶）降解的改变是导致缺血性心脏病、心力衰竭、肥胖和糖尿病中心脏脂肪酸高氧化率的重要因素。对脂肪酸氧化的额外控制也可能发生在参与线粒体脂肪酸β-氧化酶乙酰化的乙酰辅酶A水平。我们发现，脂肪酸β-氧化酶、LCAD（长链酰基辅酶A脱氢酶）和β-HAD（β-羟酰基辅酶A脱氢酶）的乙酰化与患有心力衰竭的肥胖小鼠的心脏活性和脂肪酸氧化的增加有关。这与 SIRT3（sirtuin 3）活性降低有关，SIRT3 是一种重要的线粒体脱乙酰酶。为了支持这一点，心脏 SIRT3 缺失会增加 LCAD 和 β-HAD 的乙酰化，并增加心脏脂肪酸氧化。 MCD 的乙酰化还与活性增加、丙二酰辅酶 A 水平降低和脂肪酸氧化增加有关。综合起来，这些数据表明丙二酰辅酶 A 和乙酰辅酶 A 在介导心力衰竭中脂肪酸氧化的改变方面具有重要作用。
CoA (coenzyme A) and its derivatives have a critical role in regulating cardiac energy metabolism. This includes a key role as a substrate and product in the energy metabolic pathways, as well as serving as an allosteric regulator of cardiac energy metabolism. In addition, the CoA ester malonyl-CoA has an important role in regulating fatty acid oxidation, secondary to inhibiting CPT (carnitine palmitoyltransferase) 1, a key enzyme involved in mitochondrial fatty acid uptake. Alterations in malonyl-CoA synthesis by ACC (acetylCoA carboxylase) and degradation by MCD (malonyl-CoA decarboxylase) are important contributors to the high cardiac fatty acid oxidation rates seen in ischaemic heart disease, heart failure, obesity and diabetes. Additional control of fatty acid oxidation may also occur at the level of acetyl-CoA involvement in acetylation of mitochondrial fatty acid beta-oxidative enzymes. We find that acetylation of the fatty acid beta-oxidative enzymes, LCAD (long-chain acyl-CoA dehydrogenase) and beta-HAD (beta-hydroxyacyl-CoA dehydrogenase) is associated with an increase in activity and fatty acid oxidation in heart from obese mice with heart failure. This is associated with decreased SIRT3 (sirtuin 3) activity, an important mitochondrial deacetylase. In support of this, cardiac SIRT3 deletion increases acetylation of LCAD and beta-HAD, and increases cardiac fatty acid oxidation. Acetylation of MCD is also associated with increased activity, decreases malonyl-CoA levels and an increase in fatty acid oxidation. Combined, these data suggest that malonyl-CoA and acetyl-CoA have an important role in mediating the alterations in fatty acid oxidation seen in heart failure.