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

Jan Dusek, Ivana Mejdrová, Klára Dohnalová, Tomas Smutny, Karel Chalupsky, Maria Krutakova, Josef Skoda, Azam Rashidian, Ivona Pavkova, Kryštof Škach, Jana Hricová, Michaela Chocholouskova, Lucie Smutna, Rajamanikkam Kamaraj, Miloš Hroch, Martin Leníček, Stanislav Mičuda, Dirk Pijnenburg, Rinie Beuningen, Michal Holčapek, Libor Vítek, Magnus Ingelman-Sundberg, Oliver Burk, Thales Kronenberger, Radim Nencka () and Petr Pavek ()
Additional contact information
Jan Dusek: Charles University
Ivana Mejdrová: Czech Academy of Sciences
Klára Dohnalová: Institute of Molecular Genetics of the Czech Academy of Sciences
Tomas Smutny: Charles University
Karel Chalupsky: Institute of Molecular Genetics of the Czech Academy of Sciences
Maria Krutakova: Charles University
Josef Skoda: Charles University
Azam Rashidian: Eberhard Karls University Tübingen
Ivona Pavkova: University of Defence
Kryštof Škach: Czech Academy of Sciences
Jana Hricová: Czech Academy of Sciences
Michaela Chocholouskova: University of Pardubice, Faculty of Chemical Technology
Lucie Smutna: Charles University
Rajamanikkam Kamaraj: Charles University
Miloš Hroch: Faculty of Medicine in Hradec Králové, Charles University
Martin Leníček: General University Hospital in Prague and First Faculty of Medicine, Charles University
Stanislav Mičuda: Faculty of Medicine in Hradec Králové, Charles University
Dirk Pijnenburg: PamGene
Rinie Beuningen: PamGene
Michal Holčapek: University of Pardubice, Faculty of Chemical Technology
Libor Vítek: General University Hospital in Prague and First Faculty of Medicine, Charles University
Magnus Ingelman-Sundberg: Karolinska Institutet
Oliver Burk: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen
Thales Kronenberger: Eberhard Karls University Tübingen
Radim Nencka: Czech Academy of Sciences
Petr Pavek: Charles University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56642-y

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