Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
PLoS Comput Biol. 2013;9(8):e1003186. doi: 10.1371/journal.pcbi.1003186. Epub 2013 Aug 15.
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
脂肪酸代谢在获得性和先天性代谢疾病中起着关键作用。为了深入了解脂肪酸β-氧化的网络动态，我们构建了该途径的详细计算模型，并将其置于脂肪过载条件下。该模型包含可逆和饱和的酶动力学方程以及大鼠肝脏酶的实验确定参数。通过向分离的大鼠线粒体中添加棕榈酰 CoA 或棕榈酰肉碱对其进行验证：在不重新拟合测量参数的情况下，该模型正确预测了β-氧化通量以及大多数酰基辅酶 A 浓度的时间曲线。随后，我们通过增加棕榈酰 CoA 的浓度来模拟肥胖的情况。在高浓度的棕榈酰 CoA 下，β-氧化过载：通量下降，代谢物积累。这种行为源于不同链长的酰基辅酶 A 之间的竞争，这些酰基辅酶 A 与重叠的酰基辅酶 A 脱氢酶的底物特异性竞争。这有效地诱导了竞争性的前馈抑制，从而导致辅酶 A 酯中间体的积累和游离辅酶 A（CoASH）的消耗。线粒体 [NAD⁺]/[NADH] 比调节了对底物过载的敏感性，揭示了β-氧化和线粒体呼吸之间的紧密相互作用。
