Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice

• Published in: Biochemical pharmacology Vol. 197; p. 114905
• Main Authors: Skoda, Josef, Dohnalova, Klara, Chalupsky, Karel, Stahl, Aaron, Templin, Markus, Maixnerova, Jana, Micuda, Stanislav, Grøntved, Lars, Braeuning, Albert, Pavek, Petr
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.03.2022
• Subjects: Animals; Constitutive Androstane Receptor - agonists; Constitutive Androstane Receptor - metabolism; Drug interactions; Endocrine disruptors; Hepatotoxicity; Humanized mice (HuMice); Humans; Lipid Metabolism - drug effects; Lipid Metabolism - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nuclear receptors; Pyridines - administration & dosage; Endocrine disruptors; LPE; DG; PS; EDC; HFD; PXR; FDR; mCAR; Humanized mice (HuMice); TCPOBOP; SM; Hepatotoxicity; AOP; CE; Drug interactions; Nuclear receptors; NASH; PPARs; PC; TG; CAR; PE; DPGs; FA; hCAR; LPC
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114905

[Display omitted] 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.