Acyl-CoA thioesterase-2 facilitates β-oxidation in glycolytic skeletal muscle in a lipid supply dependent manner.
Acyl-CoA thioesterase-2 facilitates β-oxidation in glycolytic skeletal muscle in a lipid supply dependent manner.
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酰基辅酶 A 硫酯酶 2 以脂质供应依赖的方式促进糖酵解骨骼肌中的 β 氧化。
DOI：
10.1101/2023.06.27.546724
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Seifert,ErinL
中科院分区：
文献类型：
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作者：
Bekeova,Carmen;Han,JiIn;Xu,Heli;Kerr,Evan;Blackburne,Brittney;Lynch,ShannonC;Mesaros,Clementina;Murgia,Marta;Vadigepalli,Rajanikanth;Beld,Joris;Leonardi,Roberta;Snyder,NathanielW;Seifert,ErinL
酰基辅酶A（酰基辅酶A）硫酯是参与线粒体基质内多种代谢反应的区室化中间体。基质中游离CoA（CoASH）的有限可用性提出了如何调节局部酰基CoA浓度以防止CoASH被任何特定底物过载捕获的问题。酰基辅酶A硫酯酶-2（ACOT 2）将长链酰基辅酶A水解为其组成脂肪酸和CoASH，并且是唯一不受CoASH抑制的线粒体基质ACOT。因此，我们推测ACOT 2可能组成性调节基质酰基辅酶A水平，当脂质供应和能量需求适度时，小鼠骨骼肌（SM）中Acot 2缺失导致酰基辅酶A积累。当能量需求和丙酮酸可用性升高时，ACOT 2活性的缺乏促进葡萄糖氧化。在Acot 2急性耗竭的C2 C12肌管中，这种对葡萄糖的偏好超过脂肪酸氧化，并且在Acot 2耗竭的糖酵解SM的分离线粒体中证明了对β-氧化的明显抑制。在喂食高脂饮食的小鼠中，ACOT 2使糖酵解SM中酰基辅酶A和神经酰胺衍生物的增加成为可能，与ACOT 2不存在时相比，这与更差的葡萄糖稳态有关。这些观察结果表明，当脂质供应适度时，ACOT 2支持CoASH可用于促进糖酵解SM中的β-氧化。然而，当脂质供应高时，ACOT 2使酰基辅酶A和脂质积累、CoASH螯合和葡萄糖稳态差成为可能。因此，ACOT 2调节糖酵解肌肉中的基质酰基辅酶A浓度，其影响取决于脂质供应。
Acyl-Coenzyme A (acyl-CoA) thioesters are compartmentalized intermediates that participate in in multiple metabolic reactions within the mitochondrial matrix. The limited availability of free CoA (CoASH) in the matrix raises the question of how the local acyl-CoA concentration is regulated to prevent trapping of CoASH from overload of any specific substrate. Acyl-CoA thioesterase-2 (ACOT2) hydrolyzes long-chain acyl-CoAs to their constituent fatty acids and CoASH, and is the only mitochondrial matrix ACOT refractory to inhibition by CoASH. Thus, we reasoned that ACOT2 may constitutively regulate matrix acyl-CoA levels.Acot2deletion in murine skeletal muscle (SM) resulted in acyl-CoA build-up when lipid supply and energy demands were modest. When energy demand and pyruvate availability were elevated, lack of ACOT2 activity promoted glucose oxidation. This preference for glucose over fatty acid oxidation was recapitulated in C2C12 myotubes with acute depletion ofAcot2, and overt inhibition of β-oxidation was demonstrated in isolated mitochondria fromAcot2-depleted glycolytic SM. In mice fed a high fat diet, ACOT2 enabled the accretion of acyl-CoAs and ceramide derivatives in glycolytic SM, and this was associated with worse glucose homeostasis compared to when ACOT2 was absent. These observations suggest that ACOT2 supports CoASH availability to facilitate β-oxidation in glycolytic SM when lipid supply is modest. However, when lipid supply is high, ACOT2 enables acyl-CoA and lipid accumulation, CoASH sequestration, and poor glucose homeostasis. Thus, ACOT2 regulates matrix acyl-CoA concentration in glycolytic muscle, and its impact depends on lipid supply.