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Sánchez Quant, E.S. ; Richter, M. ; Colomé-Tatché, M. ; Martinez Jimenez, C.P.

Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge.

Genome Biol. 24:234 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis. RESULTS: Here, we investigate the metabolic capacity of individual human hepatocytes in vitro. We assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. Using a phenotyping five-probe cocktail, we identify four functional subgroups of hepatocytes responding differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminishes the drug-related metabolic capacity of hepatocytes. CONCLUSIONS: Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups display different and heterogeneous transcriptional responses.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cytochrome P450 ; Dili ; Drug Metabolism ; Hepatic Steatosis ; Lipid Metabolism ; Liver ; Nafld ; Primary Human Hepatocytes ; Single-cell Transcriptomics; Fatty Liver-disease; Gene-expression; Transcriptional Regulation; Cytochrome-p450 Probes; Hepatic Steatosis; Enzymes; Cocktail; Mechanisms; Midazolam; Risk
ISSN (print) / ISBN 1474-760X
e-ISSN 1465-6906
Zeitschrift Genome Biology
Quellenangaben Band: 24, Heft: 1, Seiten: , Artikelnummer: 234 Supplement: ,
Verlag BioMed Central
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Pioneer Campus (HPC)
Institute of Computational Biology (ICB)
Förderungen Impuls-und Vernetzungsfonds of the Helmholtz-Gemeinschaft
C.P.M-J at the Helmholtz Pioneer Campus
Projekt DEAL