The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
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 re...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56642-y |
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| author | 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 van Beuningen Michal Holčapek Libor Vítek Magnus Ingelman-Sundberg Oliver Burk Thales Kronenberger Radim Nencka Petr Pavek |
| author_facet | 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 van Beuningen Michal Holčapek Libor Vítek Magnus Ingelman-Sundberg Oliver Burk Thales Kronenberger Radim Nencka Petr Pavek |
| author_sort | Jan Dusek |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-09b5e193d59b441aa102638cfd4d1e22 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-09b5e193d59b441aa102638cfd4d1e222025-02-09T12:44:26ZengNature PortfolioNature Communications2041-17232025-02-0116112110.1038/s41467-025-56642-yThe hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia modelJan Dusek0Ivana Mejdrová1Klára Dohnalová2Tomas Smutny3Karel Chalupsky4Maria Krutakova5Josef Skoda6Azam Rashidian7Ivona Pavkova8Kryštof Škach9Jana Hricová10Michaela Chocholouskova11Lucie Smutna12Rajamanikkam Kamaraj13Miloš Hroch14Martin Leníček15Stanislav Mičuda16Dirk Pijnenburg17Rinie van Beuningen18Michal Holčapek19Libor Vítek20Magnus Ingelman-Sundberg21Oliver Burk22Thales Kronenberger23Radim Nencka24Petr Pavek25Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityInstitute of Organic Chemistry and Biochemistry, Czech Academy of SciencesCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityCzech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of SciencesDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University TübingenMilitary Faculty of Medicine, University of DefenceInstitute of Organic Chemistry and Biochemistry, Czech Academy of SciencesInstitute of Organic Chemistry and Biochemistry, Czech Academy of SciencesDepartment of Analytical Chemistry, University of Pardubice, Faculty of Chemical TechnologyDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityDepartment of Biochemistry, Faculty of Medicine in Hradec Králové, Charles UniversityInstitute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and First Faculty of Medicine, Charles UniversityInstitute of Pharmacology, Faculty of Medicine in Hradec Králové, Charles UniversityPamGenePamGeneDepartment of Analytical Chemistry, University of Pardubice, Faculty of Chemical TechnologyInstitute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague and First Faculty of Medicine, Charles UniversitySection of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska InstitutetDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of TuebingenInstitute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University TübingenInstitute of Organic Chemistry and Biochemistry, Czech Academy of SciencesDepartment of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56642-y |
| spellingShingle | 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 van Beuningen Michal Holčapek Libor Vítek Magnus Ingelman-Sundberg Oliver Burk Thales Kronenberger Radim Nencka Petr Pavek The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model Nature Communications |
| title | The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model |
| title_full | The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model |
| title_fullStr | The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model |
| title_full_unstemmed | The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model |
| title_short | The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model |
| title_sort | hypolipidemic effect of mi 883 the combined car agonist pxr antagonist in diet induced hypercholesterolemia model |
| url | https://doi.org/10.1038/s41467-025-56642-y |
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