Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• Cholesterol metabolism   blood   MeSH
• Cytochrome P-450 CYP3A genetics   metabolism   MeSH
• Diet, High-Fat adverse effects   MeSH
• Hypercholesterolemia * drug therapy   metabolism   etiology   MeSH
• Hypolipidemic Agents * pharmacology   therapeutic use   MeSH
• Liver metabolism   drug effects   MeSH
• Constitutive Androstane Receptor MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Pregnane X Receptor * antagonists & inhibitors   metabolism   genetics   MeSH
• Receptors, Cytoplasmic and Nuclear * agonists   metabolism   genetics   antagonists & inhibitors   MeSH
• Bile Acids and Salts metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• Cytochrome P-450 CYP3A MeSH
• Hypolipidemic Agents * MeSH
• Constitutive Androstane Receptor MeSH
• Pregnane X Receptor * MeSH
• Receptors, Cytoplasmic and Nuclear * MeSH
• Bile Acids and Salts MeSH