Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global ¹³C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system.

肝脏代谢是人类生理学的核心，并影响常见代谢性疾病的发病机制。然而，我们对人类肝脏代谢的理解仍然不完整，目前的大部分知识都基于动物或细胞培养模型，并不能完全概括人类生理学。在这里，我们使用全局 ¹³C 示踪、非靶向质谱和基于模型的代谢通量分析对完整人肝组织离体代谢进行深入测量。同位素示踪允许在单个实验中对广泛的代谢途径进行定性评估，证实了肝脏代谢的已知特征，但也揭示了意想不到的代谢活动，例如从头肌酸合成和支链氨基酸转氨反应，其中人类肝脏似乎与啮齿动物模型不同。离体葡萄糖产生与供体血浆葡萄糖相关，表明培养的肝组织保留了个体代谢表型，并且可以通过餐后营养物质和胰岛素水平以及糖原利用的药理学抑制来抑制。离体同位素示踪允许在实验可处理的系统中以极高的深度和分辨率测量人体肝脏代谢。