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
Download full text from publisher
Most related items
These are the items that most often cite the same works as this one and are cited by the same works as this one.
- Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024.
"Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR,"
Nature Communications, Nature, vol. 15(1), pages 1-14, December.
- Shengjie Fan & Yingxuan Yan & Ying Xia & Zhenyu Zhou & Lingling Luo & Mengnan Zhu & Yongli Han & Deqiang Yao & Lijun Zhang & Minglv Fang & Lina Peng & Jing Yu & Ying Liu & Xiaoyan Gao & Huida Guan & H, 2023.
"Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions,"
Nature Communications, Nature, vol. 14(1), pages 1-23, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56642-y. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.