Journal Article

The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model

Chocholouskova, Michaela, Vítek, Libor, Smutny, Tomas, Smutna, Lucie, Kamaraj, Rajamanikkam, Mičuda, Stanislav, Škach, Kryštof, Pavek, Petr, Kronenberger, Thales, Hroch, Miloš, Chalupsky, Karel, Leníček, Martin, Dohnalová, Klára, Hricová, Jana, Pavkova, Ivona, Mejdrová, Ivana, Dusek, Jan, Holčapek, Michal, Rashidian, Azam, Skoda, Josef, Pijnenburg, Dirk, van Beuningen, Rinie, Krutakova, Maria, Ingelman-Sundberg, Magnus, Burk, Oliver, Nencka, Radim

2025

Overview

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. CAR and PXR receptors are known to regulate metabolism, however, there is no dual human ligand suitable for therapy. Here, the authors show a CAR agonist/PXR antagonist, MI-883, which regulates cholesterol/bile acid homeostasis by leveraging CAR and PXR activations in plasma cholesterol regulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 38/77 / 38/91 / 631/154/436/2387 / 631/337/572/2102 / 64/110 / 64/60 / 692/308/2778 / 692/308/575 / 96/109 / Acids / Agonists / Animals / Bile / Bile Acids and Salts - metabolism / Cholesterol / Cholesterol - blood / Cholesterol - metabolism / Constitutive Androstane Receptor / Cytochrome P-450 CYP3A - genetics / Cytochrome P-450 CYP3A - metabolism / Diet / Diet, High-Fat - adverse effects / Disease Models, Animal / Fatty liver / Gene regulation / High cholesterol diet / High fat diet / Homeostasis / Humanities and Social Sciences / Humans / Hypercholesterolemia / Hypercholesterolemia - drug therapy / Hypercholesterolemia - etiology / Hypercholesterolemia - metabolism / Hypolipidemic Agents - pharmacology / Hypolipidemic Agents - therapeutic use / Ligands / Lipid metabolism / Liver / Liver - drug effects / Liver - metabolism / Liver diseases / Male / Metabolic disorders / Metabolism / Metabolomics / Mice / Mice, Inbred C57BL / multidisciplinary / Nuclear receptors / Pregnane X Receptor - antagonists & inhibitors / Pregnane X Receptor - genetics / Pregnane X Receptor - metabolism / Pregnane X receptors / Receptors / Receptors, Cytoplasmic and Nuclear - agonists / Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors / Receptors, Cytoplasmic and Nuclear - genetics / Receptors, Cytoplasmic and Nuclear - metabolism / Science / Science (multidisciplinary) / Steatosis / Transcriptomics