The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
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.
Authors
- Magnus Ingelman‐Sundberg (ORCID: https://orcid.org/0000-0002-7255-9079)
- Klára Dohnalová
- Karel Chalupský (ORCID: https://orcid.org/0000-0001-6890-6464)
- Michaela Chocholoušková
- Radim Nencka (ORCID: https://orcid.org/0000-0001-6167-0380)
- Oliver Burk (ORCID: https://orcid.org/0000-0001-8990-9656)
- Rajamanikkam Kamaraj (ORCID: https://orcid.org/0000-0001-7115-0178)
- Josef Škoda (ORCID: https://orcid.org/0000-0003-0225-0727)
- Petr Pávek (ORCID: https://orcid.org/0000-0001-8769-4196)
- M Hroch (ORCID: https://orcid.org/0000-0002-5583-2942)
- Stanislav Mičuda (ORCID: https://orcid.org/0000-0002-7773-7161)
- Lucie Smutná (ORCID: https://orcid.org/0000-0002-3941-4193)
- Michal Holčapek (ORCID: https://orcid.org/0000-0003-3978-1249)
- Ivana Mejdrová (ORCID: https://orcid.org/0009-0007-1587-9811)
- Tomáš Smutný (ORCID: https://orcid.org/0000-0001-5788-7413)
- Jana Hricová (ORCID: https://orcid.org/0009-0008-9369-8853)
- Rinie van Beuningen
- Azam Rashidian
- Ivona Pávková (ORCID: https://orcid.org/0000-0001-8241-479X)
- Dirk Pijnenburg
- Thales Kronenberger (ORCID: https://orcid.org/0000-0001-6933-7590)
- Martin Leníček (ORCID: https://orcid.org/0000-0001-6242-3488)
- Libor Vı́tek (ORCID: https://orcid.org/0000-0002-5318-0151)
- Kryštof Škach (ORCID: https://orcid.org/0000-0002-7558-6961)
- Ján Dušek (ORCID: https://orcid.org/0000-0002-1946-4994)
- Mária Krutáková
Institutions
- University of Pardubice (CZ)
- University of Eastern Finland (FI)
- Charles University (CZ)
- Karolinska Institutet (SE)
- Institute of Organic Chemistry (PL)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- PamGene (Netherlands) (NL)
- University Hospital Hradec Králové (CZ)
- Czech Academy of Sciences, Institute of Molecular Genetics (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- General University Hospital in Prague (CZ)
- Institute of Pharmacology (CZ)
- University of Hradec Králové (CZ)
- University of Tübingen (DE)
- University of Defence (CZ)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1038/s41467-025-56642-y
- Citations
- 9
- Primary Topic
- Pharmacogenetics and Drug Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 14.02
Funders
- Univerzita Karlova v Praze
- Itä-Suomen Yliopisto
- European Commission
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Grantová Agentura České Republiky
- Bundesministerium für Bildung und Forschung
- Karolinska Institutet
- Akademie Věd České Republiky
- China Scholarship Council
- Ministerstvo Obrany České Republiky
- Univerzita Pardubice
- Všeobecná Fakultní Nemocnice v Praze
- Ústav Molekulární Genetiky, Akademie Věd České Republiky
- lékařská fakulta Univerzity Karlovy
- Ústav organické chemie a biochemie Akademie věd České republiky