MI-883 Constitutes a Novel Dual-Action Ligand Targeting Constitutive Androstane Receptor and Pregnane X Receptor for Hypercholesterolemia Intervention

We describe the effect of a novel combined human CAR agonist/PXR antagonist MI-883 on the liver transcriptome. RNA-seq transcriptomic data in control (n=5) and MI-883-treated (n=5) humanized PXR-CAR-CYP3A4/3A7 male mice fed with high-fat diet demonstrate that MI-883 significantly regulates genes involved in xenobiotic metabolism, and fatty acid and cholesterol homeostasis. This compound thus reduces plasma cholesterol levels and enhances fecal bile acid excretion. Overall design: Humanized PXR-CAR-CYP3A4/3A7 mice were fed with high-fat diet. Then animals were treated with either MI-883 treatment or vehicle in p.o. gavage. Liver tissue was used dor transcriptomic analysis. Differential expression analysis of liver transcriptome of humanized PXR-CAR-CYP3A4/3A7 mice fed with high fat diet after treatment with MI-883. GO pathway analysis of metabolic processes in the liver of of humanized PXR-CAR-CYP3A4/3A7 mice after treatment with MI-883 (n=5) and control mice (vehicle-treated, n=5).