A comparison between different human hepatocyte models reveals profound differences in net glucose production, lipid composition and metabolism in vitro
Experimental Cell Research, vol. 437, pp. 114008
Abstract
Hepatocytes are responsible for maintaining a stable blood glucose concentration during periods of nutrient scarcity. The breakdown of glycogen and de novo 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 in vitro studies and have been instrumental in elucidating key aspects of energy metabolism found in vivo. 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 G6PC and PCK1 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.
Authors 7
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Affiliation as printed
Mimetas, Leiden, Netherlands
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Affiliation as printed
Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Netherlands
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Science for Life Laboratory · KTH Royal Institute of Technology
Affiliation as printed
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
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Affiliation as printed
Mimetas, Leiden, Netherlands
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Affiliation as printed
Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Netherlands
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Science for Life Laboratory · KTH Royal Institute of Technology
Affiliation as printed
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
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Thomas Hankemeier corresponding Aachen Metabolomics and Analytics Centre Leiden Academic Centre for Drug Research
Affiliation as printed
Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Netherlands. Electronic address: f.bonanini@mimetas.com
Metabolomics and Analytics Center, Leiden Academic Centre for Drug Research, Leiden University, Netherlands
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