Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD.
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DOI：
10.15252/msb.20167422
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发表时间：
2017-03-02
影响因子：
9.9
通讯作者：
Boren J
中科院分区：
文献类型：
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作者：
Mardinoglu A;Bjornson E;Zhang C;Klevstig M;Söderlund S;Ståhlman M;Adiels M;Hakkarainen A;Lundbom N;Kilicarslan M;Hallström BM;Lundbom J;Vergès B;Barrett PH;Watts GF;Serlie MJ;Nielsen J;Uhlén M;Smith U;Marschall HU;Taskinen MR;Boren J
为了阐明非酒精性脂肪肝 (NAFLD) 的分子机制，我们招募了 86 名患有不同程度肝脂肪变性 (HS) 的受试者。我们获得了脂蛋白通量的实验数据，并使用这些单独的测量结果作为肝细胞基因组规模代谢模型的个性化约束，以研究肝脏的代谢差异，同时考虑到其与其他组织的相互作用。我们的系统级分析预测高 HS 受试者对 NAD + 和谷胱甘肽 (GSH) 的需求发生变化。我们的分析和代谢组学测量表明，甘氨酸、丝氨酸和相关代谢物的血浆水平与 HS 呈负相关，表明这些 GSH 代谢前体可能具有限制性。相关酶的肝脏表达水平的量化进一步表明谷胱甘肽从头合成发生了改变。为了评估补充 GSH 和 NAD+ 对 NAFLD 发展的影响，我们在西方饮食中添加了 GSH 和 NAD+ 生物合成的前体，并证明补充可以预防小鼠的 HS。在一项概念验证人体研究中，我们发现补充丝氨酸（甘氨酸的前体）后肝功能得到改善，HS 降低，并在此提出 NAFLD 治疗策略。
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.