论文标题

转囊化在细胞内脂解和相关QSSA近似中的潜在作用

The potential roles of transacylation in intracellular lipolysis and related QSSA approximations

论文作者

Elias, Jan, Fellner, Klemens, Hofer, Peter, Oberer, Monika, Schreiber, Renate, Zechner, Rudolf

论文摘要

脂肪酸(FAS)是至关重要的能量代谢产物,信号分子和膜构建块,用于广泛的生物。脂肪甘油三酸酯脂肪酶(ATGL)是从胞质脂质液滴中存储的三酰基甘油(TGS)中FA释放的最关键调节剂。然而,除了将TGs水解为二酰基甘油(DGS)的功能外,ATGL还促进了两个DG分子的转囊反应到一个TG和一个单酰基甘油分子。迄今为止,尚不清楚DG transacylation是否是ATGL介导的脂肪分解的巧合副产品,还是它在生理上是相关的。实验证据是稀缺的,因为水解和透射率都依赖于ATGL的相同活性位点,并且始终在分子集合中并行。 本文说明了跨囊化的潜在作用。它表明,取决于动力学参数,但也取决于水解机制的状态,transacylation可以增加或降低下游产物最高50 \%等。我们提供广泛的渐近分析,包括具有高阶校正项的准稳态近似(QSSA)并提供数值模拟。我们还认为,在评估QSSA的有效性时,应包括参数灵敏度衍生物。我们的结果表明,ATGL的转囊功能通过为脂肪细胞中的脂肪溶解机械提供反馈选择和完全稳定性而具有生物学相关性。

Fatty acids (FAs) are crucial energy metabolites, signalling molecules, and membrane building blocks for a wide range of organisms. Adipose triglyceride lipase (ATGL) is the first and presumingly most crucial regulator of FA release from triacylglycerols (TGs) stored within cytosolic lipid droplets. However, besides the function of releasing FAs by hydrolysing TGs into diacylglycerols (DGs), ATGL also promotes the transacylation reaction of two DG molecules into one TG and one monoacylglycerol molecule. To date, it is unknown whether DG transacylation is a coincidental byproduct of ATGL-mediated lipolysis or whether it is physiologically relevant. Experimental evidence is scarce since both, hydrolysis and transacylation, rely on the same active site of ATGL and always occur in parallel in an ensemble of molecules. This paper illustrates the potential roles of transacylation. It shows that, depending on the kinetic parameters but also on the state of the hydrolytic machinery, transacylation can increase or decrease downstream products up to 50\% and more. We provide an extensive asymptotic analysis including quasi-steady-state approximations (QSSA) with higher order correction terms and provide numerical simulation. We also argue that when assessing the validity of QSSAs one should include parameter sensitivity derivatives. Our results suggest that the transacylation function of ATGL is of biological relevance by providing feedback options and altogether stability to the lipolytic machinery in adipocytes.

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