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

  • Nat Commun. 2025 Feb 6;16(1):1418. doi: 10.1038/s41467-025-56642-y.
Jan Dusek  #  1 ,  Ivana Mejdrová  #  2 ,  Klára Dohnalová  3  4 ,  Tomas Smutny  1 ,  Karel Chalupsky  3 ,  Maria Krutakova  1 ,  Josef Skoda  1 ,  Azam Rashidian  5 ,  Ivona Pavkova  6 ,  Kryštof Škach  2 ,  Jana Hricová  2 ,  Michaela Chocholouskova  7 ,  Lucie Smutna  1 ,  Rajamanikkam Kamaraj  1 ,  Miloš Hroch  8 ,  Martin Leníček  9 ,  Stanislav Mičuda  10 ,  Dirk Pijnenburg  11 ,  Rinie van Beuningen  11 ,  Michal Holčapek  7 ,  Libor Vítek  9  12 ,  Magnus Ingelman-Sundberg  13 ,  Oliver Burk  14 ,  Thales Kronenberger  5  15 ,  Radim Nencka  16 ,  Petr Pavek  17
Affiliations
  • 1. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
  • 2. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • 3. Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 4. First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 5. Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Tübingen, Germany.
  • 6. Military Faculty of Medicine, University of Defence, Hradec Králové, Czech Republic.
  • 7. Department of Analytical Chemistry, University of Pardubice, Faculty of Chemical Technology, Pardubice, Czech Republic.
  • 8. Department of Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
  • 9. Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 10. Institute of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
  • 11. PamGene, 's-Hertogenbosch, The Netherlands.
  • 12. 4th Department of Internal Medicine, General University Hospital in Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 13. Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • 14. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany.
  • 15. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
  • 16. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic. [email protected].
  • 17. Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. [email protected].
  • # Contributed equally.
PMID: 39915454 DOI: 10.1038/s41467-025-56642-y
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.

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