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

Author

Listed:
  • Jan Dusek

    (Charles University)

  • Ivana Mejdrová

    (Czech Academy of Sciences)

  • Klára Dohnalová

    (Institute of Molecular Genetics of the Czech Academy of Sciences
    Charles University)

  • 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
    4th Department of Internal Medicine, 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
    University of Eastern Finland)

  • Radim Nencka

    (Czech Academy of Sciences)

  • Petr Pavek

    (Charles University)

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.

Suggested Citation

  • Jan Dusek & Ivana Mejdrová & Klára Dohnalová & Tomas Smutny & Karel Chalupsky & Maria Krutakova & Josef Skoda & Azam Rashidian & Ivona Pavkova & Kryštof Škach & Jana Hricová & Michaela Chocholouskova , 2025. "The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56642-y
    DOI: 10.1038/s41467-025-56642-y
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    References listed on IDEAS

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    1. Wenwei Lin & Yue-Ming Wang & Sergio C. Chai & Lili Lv & Jie Zheng & Jing Wu & Qijun Zhang & Yong-Dong Wang & Patrick R. Griffin & Taosheng Chen, 2017. "SPA70 is a potent antagonist of human pregnane X receptor," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
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