Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines
Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines
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DOI：
10.1038/s41467-020-15058-6
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发表时间：
2020-03-13
影响因子：
16.6
通讯作者：
Verfaillie, Catherine M.
中科院分区：
文献类型：
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作者：
Boon, Ruben;Kumar, Manoj;Verfaillie, Catherine M.
在临床前环境中预测药物诱导的肝损伤仍然具有挑战性，因为原代人肝细胞（PHHs）、多能干细胞衍生的类肝细胞（HLCs）以及肝癌细胞都表现出较差的药物生物转化能力。在此我们证明，肝功能更多地取决于细胞代谢和细胞外营养物质，而非发育调节因子。具体而言，我们证明，使细胞外氨基酸增加超过HLCs和HepG2细胞的营养需求，会诱导葡萄糖独立性、线粒体功能，并使转录图谱更接近PHHs。此外，我们表明这些高水平的氨基酸足以使HLC和HepG2的药物生物转化以及对肝毒素的敏感性达到与PHHs相似的水平。总之，我们提供的数据表明细胞外营养物质水平是细胞成熟的一个主要决定因素，并且可用于指导干细胞向肝系分化。
Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.