Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
34971590
DOI
10.1016/j.bcp.2021.114905
PII: S0006-2952(21)00531-1
Knihovny.cz E-zdroje
- Klíčová slova
- Drug interactions, Endocrine disruptors, Hepatotoxicity, Humanized mice (HuMice), Nuclear receptors,
- MeSH
- konstitutivní androstanový receptor agonisté metabolismus MeSH
- lidé MeSH
- metabolismus lipidů účinky léků fyziologie MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- pyridiny aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 1,4-bis(2-(3,5-dichloropyridyloxy))benzene MeSH Prohlížeč
- konstitutivní androstanový receptor MeSH
- pyridiny MeSH
The constitutive androstane receptor (CAR) controls xenobiotic clearance, regulates liver glucose, lipid metabolism, and energy homeostasis. These functions have been mainly discovered using the prototypical mouse-specific CAR ligand TCPOBOP in wild-type or CAR null mice. However, TCPOBOP is reported to result in some off-target metabolic effects in CAR null mice. In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyses in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the model, human CAR retains its constitutive activity in metabolism regulation; however, it is not activated by TCPOBOB. Notably, we observed that TCPOBOP affected lipid homeostasis by elevating serum and liver triglyceride levels and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and decrease of its metabolites in humanized CAR mice. RNA-seq analysis has shown divergent gene expression levels in wild-type and humanized CAR mice. Gene expression regulation in humanized mice is mainly involved in lipid metabolic processes and in the PPAR, leptin, thyroid, and circadian clock pathways. In contrast, CAR activation by TCPOBOP in wild-type mice reduced liver and plasma triglyceride levels and induced a typical transcriptomic proliferative response in the liver. In summary, we identified TCPOBOP as a disruptor of lipid metabolism in humanized CAR mice. The divergent effects of TCPOBOP in humanized mice in comparison with the prototypical CAR-mediated response in WT mice warrant the use of appropriate model ligands and humanized animal models during the testing of endocrine disruption and the characterization of adverse outcome pathways.
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