NMR-based metabolomic profiling reveals distinct metabolic signatures of primary hepatocytes and hepatocellular carcinoma cell lines.

Authors

Corentine Goossens, Vincent Tambay, Valérie-Ann Raymond, Marc Bilodeau

Published in

PloS one. Volume 21. Issue 11. Pages e0361879. Epub Nov 12, 2026.

Abstract

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming that supports tumor initiation, growth, and metastasis. Understanding how metabolic profiles differ between normal hepatocytes and HCC cells with distinct aggressive phenotypes may help identify metabolic features associated with tumor progression. The Dt81Hepa1-6 cell line, derived from the murine Hepa1-6 hepatoma line, exhibits increased aggressiveness and provides a useful model for investigating metabolic features associated with aggressive behavior. We performed an integrative 1H NMR-based metabolomic analysis of intracellular extracts (endometabolome) and extracellular culture media (exometabolome) from primary hepatocytes, Hepa1-6, and Dt81Hepa1-6 cells collected at 24h and 48h. Multivariate statistical analyses, including PCA and PLS-DA, were used to characterize metabolic differences among the three cell types. Metabolic profiling revealed a clear separation between primary hepatocytes and HCC cells in both endometabolomic and exometabolomic datasets. HCC cells exhibited increased lactate and alanine levels together with decreased intracellular glucose and glutathione, consistent with altered glycolytic and redox metabolism. Time-dependent changes in glucose consumption and lactate release were prominent in extracellular media from both HCC cell lines. The aggressive Dt81Hepa1-6 line displayed a distinct metabolic phenotype characterized by increased extracellular pyroglutamate, citrate, formate and particularly BCAA-derived ketoacids, 2-oxo-isovalerate and 3-methyl-2-oxovalerate. These findings are consistent with alterations in BCAA-associated metabolism, glutamine/glutamate, and TCA-related metabolism in the more aggressive cell line. Overall, the integration of endometabolomic and exometabolomic 1H NMR profiling identifies metabolic features associated with the aggressive phenotype of Dt81Hepa1-6 cells. BCAA-derived ketoacids, pyroglutamate, and TCA-related metabolites emerge as candidate metabolic features that warrant validation in additional experimental and clinical HCC models.

PMID:
43019349
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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