Hepatocytes are responsible for maintaining a stable blood glucose concentration during periods of nutrient scarcity. The breakdown of glycogen and synthesis of glucose are crucial metabolic pathways deeply interlinked with lipid metabolism. Alterations in these pathways are often associated with metabolic diseases with serious clinical implications. Studying energy metabolism in human cells is challenging. Primary hepatocytes are still considered the golden standard for studies and have been instrumental in elucidating key aspects of energy metabolism found . As a result of several limitations posed by using primary cells, a multitude of alternative hepatocyte cellular models emerged as potential substitutes. Yet, there remains a lack of clarity regarding the precise applications for which these models accurately reflect the metabolic competence of primary hepatocytes. In this study, we compared primary hepatocytes, stem cell-derived hepatocytes, adult donor-derived liver organoids, immortalized Upcyte-hepatocytes and the hepatoma cell line HepG2s in their response to a glucose production challenge. We observed the highest net glucose production in primary hepatocytes, followed by organoids, stem-cell derived hepatocytes, Upcyte-hepatocytes and HepG2s. Glucogenic gene induction was observed in all tested models, as indicated by an increase in and expression. Lipidomic analysis revealed considerable differences across the models, with organoids showing the closest similarity to primary hepatocytes in the common lipidome, comprising 347 lipid species across 19 classes. Changes in lipid profiles as a result of the glucose production challenge showed a variety of, and in some cases opposite, trends when compared to primary hepatocytes.

中文翻译：

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不同人类肝细胞模型之间的比较揭示了体外净葡萄糖产生、脂质组成和代谢的巨大差异

肝细胞负责在营养缺乏期间维持稳定的血糖浓度。糖原的分解和葡萄糖的合成是与脂质代谢密切相关的重要代谢途径。这些途径的改变通常与具有严重临床意义的代谢疾病相关。研究人体细胞的能量代谢具有挑战性。原代肝细胞仍然被认为是研究的黄金标准，并有助于阐明所发现的能量代谢的关键方面。由于使用原代细胞带来的一些限制，出现了多种替代肝细胞模型作为潜在的替代品。然而，这些模型准确反映原代肝细胞代谢能力的精确应用仍然缺乏明确性。在这项研究中，我们比较了原代肝细胞、干细胞衍生的肝细胞、成人供体衍生的肝脏类器官、永生化Upcyte肝细胞和肝癌细胞系HepG2s对葡萄糖产生挑战的反应。我们观察到原代肝细胞的净葡萄糖产量最高，其次是类器官、干细胞衍生的肝细胞、Upcyte 肝细胞和 HepG2。在所有测试模型中均观察到生糖基因诱导，如表达增加所示。脂质组学分析揭示了模型之间存在相当大的差异，类器官与常见脂质组中的原代肝细胞最相似，包括 19 个类别的 347 种脂质。与原代肝细胞相比，葡萄糖产生挑战导致的脂质谱变化显示出多种趋势，在某些情况下甚至相反。