From the Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine, California 92697.
J Biol Chem. 2014 Feb 28;289(9):6091-7. doi: 10.1074/jbc.M113.537191. Epub 2014 Jan 14.
The circadian clock regulates a wide range of physiological and metabolic processes, and its disruption leads to metabolic disorders such as diabetes and obesity. Accumulating evidence reveals that the circadian clock regulates levels of metabolites that, in turn, may regulate the clock. Here we demonstrate that the circadian clock regulates the intracellular levels of acetyl-CoA by modulating the enzymatic activity of acetyl-CoA Synthetase 1 (AceCS1). Acetylation of AceCS1 controls the activity of the enzyme. We show that acetylation of AceCS1 is cyclic and that its rhythmicity requires a functional circadian clock and the NAD(+)-dependent deacetylase SIRT1. Cyclic acetylation of AceCS1 contributes to the rhythmicity of acetyl-CoA levels both in vivo and in cultured cells. Down-regulation of AceCS1 causes a significant decrease in the cellular acetyl-CoA pool, leading to reduction in circadian changes in fatty acid elongation. Thus, a nontranscriptional, enzymatic loop is governed by the circadian clock to control acetyl-CoA levels and fatty acid synthesis.
生物钟调节广泛的生理和代谢过程，其紊乱会导致代谢紊乱，如糖尿病和肥胖症。越来越多的证据表明，生物钟调节代谢物的水平，而代谢物反过来又可能调节生物钟。在这里，我们证明生物钟通过调节乙酰辅酶 A 合酶 1（AceCS1）的酶活性来调节细胞内乙酰辅酶 A 的水平。AceCS1 的乙酰化控制着酶的活性。我们表明，AceCS1 的乙酰化是周期性的，其节律性需要一个功能性的生物钟和 NAD(+)依赖的去乙酰化酶 SIRT1。AceCS1 的周期性乙酰化有助于体内和培养细胞中乙酰辅酶 A 水平的节律性。AceCS1 的下调会导致细胞内乙酰辅酶 A 池显著减少，从而导致脂肪酸延长过程中的昼夜变化减少。因此，非转录酶促环由生物钟控制，以控制乙酰辅酶 A 水平和脂肪酸合成。
