The global effect of naturally occurring metabolic cofactor supplementation

The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically and there is no approved medication for its treatment. Recently, we revealed the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic co-factors that might be beneficial as supplements to decrease fat in human liver. Here, we first assessed the tolerability of the combined metabolic cofactors including L-serine, N acetyl-L-cysteine (NAC), nicotinamide riboside (NR) and L-carnitine by performing a 7-day rat toxicology study. Second, we performed a 5-day human calibration study by supplementing metabolic cofactors and measured the kinetics of these metabolites in the plasma of nine subjects. We measured clinical parameters and observed no immediate side effects. Next, we generated untargeted metabolomics data to reveal the changes associated with the supplementation of these metabolic cofactors using genome-scale metabolic modelling and observed that such supplementation is significantly associated with lipid, amino acid and anti-oxidant metabolism. Finally, we generated an ordinary differential equation model to predict blood concentrations during daily long-term supplementation of these compounds and liver concentrations using pharmacokinetic modeling to adjust the doses of individual metabolic cofactors in human clinical studies.

非酒精性脂肪性肝病（NAFLD）的患病率持续显著上升，而目前尚无获批的治疗药物。近期，我们通过网络分析揭示了NAFLD进展的潜在分子机制，并确定了可能作为补充剂降低人类肝脏脂肪的代谢共因子。在本研究中，我们首先通过进行为期7天的大鼠毒性研究评估了包括L-丝氨酸、N-乙酰-L-半胱氨酸（NAC）、烟酰胺核糖苷（NR）和L-肉碱在内的联合代谢共因子的耐受性。其次，我们通过补充代谢共因子进行了为期5天的人体校准研究，并测量了9名受试者血浆中这些代谢物的动力学。我们测量了临床参数，并观察到没有立即的副作用。随后，我们生成了非靶向代谢组学数据，利用基因组级代谢建模揭示了与这些代谢共因子补充相关的变化，并观察到这种补充与脂质、氨基酸和抗氧化代谢的显著关联。最后，我们利用药代动力学建模生成了一个常微分方程模型，以预测在每日长期补充这些化合物期间的血液浓度和肝脏浓度，并调整人类临床研究中个体代谢共因子的剂量。