To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

中文翻译：

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个人模型辅助识别NAD +和谷胱甘肽代谢作为NAFLD的干预目标。

为了阐明非酒精性脂肪肝疾病（NAFLD）的分子机制，我们招募了86名不同程度的肝脂肪变性（HS）的受试者。我们获得了有关脂蛋白通量的实验数据，并将这些单独的测量值用作肝细胞基因组规模代谢模型的个性化约束条件，以考虑肝脏与其他组织的相互作用来研究肝脏的代谢差异。我们的系统水平分析预测高HS受试者对NAD +和谷胱甘肽（GSH）的需求将发生变化。我们的分析和代谢组学测量表明，血浆甘氨酸，丝氨酸及相关代谢产物与HS呈负相关，表明这些GSH代谢前体可能限制。相关酶的肝表达水平的定量进一步指出了从头GSH合成的改变。为了评估GSH和NAD +补充对NAFLD发育的影响，我们向西方饮食中添加了GSH和NAD +生物合成的前体，并证明了补充可以预防小鼠的HS。在一项概念验证的人体研究中，我们发现在补充丝氨酸（甘氨酸的前体）后，肝脏功能得到改善，HS降低，因此提出了NAFLD治疗策略。