The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. 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 human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.

中文翻译：

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代谢辅因子补充的急性作用：针对非酒精性脂肪肝病的潜在治疗策略。


非酒精性脂肪肝（NAFLD）的患病率持续急剧增加，并且尚无批准的治疗药物。最近，我们利用网络分析预测了 NAFLD 进展的潜在分子机制，并确定了可能有益于减少人类肝脏脂肪补充剂的代谢辅助因子。在这里，我们首先通过进行为期 7 天的大鼠毒理学研究来评估组合代谢辅因子（包括 L-丝氨酸、N-乙酰-L-半胱氨酸（NAC）、烟酰胺核苷（NR）和 L-肉碱）的耐受性。其次，我们通过补充组合代谢辅因子进行了人体校准研究，并进行了一项对照研究，以研究有或没有补充的健康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没有观察到立即的副作用。接下来，我们生成了血浆代谢组学和炎症蛋白标记物数据，以揭示与补充代谢辅因子相关的急性变化。我们还使用个性化基因组规模代谢模型整合代谢组学数据，并观察到这种补充剂显着影响全球人类脂质、氨基酸和抗氧化剂代谢。最后，我们通过生成常微分方程模型来预测这些化合物在日常长期补充期间的血液浓度，并通过生成药代动力学模型来预测丝氨酸的肝脏浓度，并最终为未来的人体临床试验调整各个代谢辅因子的剂量。