Omics analyses of mouse constitutive androstane receptor (CAR) ligand TCPOBOP effects in humanized mice reveal off-target lipid metabolism disruption

In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyzes in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the humanized mouse model, human CAR retains its constitutive activity in metabolism regulation; however, it is not significantly activated by TCPOBOB. TCPOBOP elevated serum and liver levels of triglycerides and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and downregulation of its metabolites in humanized CAR mice. RNA-seq analysis has shown gene expression changes mainly involved in lipid metabolic processes and in ppar, leptine, thyroid, and circadian clock pathways. In summary, we identify TCPOBOP as a lipid metabolism disruptor in humanized CAR mice RNA-seq was performed on C57BL/6 Ntac and humanized PXR-CAR-CYP3A4/3A7 mice liver harvested after 48 hours of TCPOBOP treatment (2 afministrations after 24 hour, 3mg/kg, n=4).