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The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
J. Dusek, I. Mejdrová, K. Dohnalová, T. Smutny, K. Chalupsky, M. Krutakova, J. Skoda, A. Rashidian, I. Pavkova, K. Škach, J. Hricová, M. Chocholouskova, L. Smutna, R. Kamaraj, M. Hroch, M. Leníček, S. Mičuda, D. Pijnenburg, R. van Beuningen, M....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články
Grantová podpora
TuCAD2 and CMIF
Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
NLK
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2019-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2019-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
Springer Nature OA/Free Journals
od 2010-12-01
Springer Nature - nature.com Journals - Fully Open Access
od 2010-12-01
- MeSH
- cholesterol * metabolismus krev MeSH
- cytochrom P-450 CYP3A metabolismus genetika MeSH
- dieta s vysokým obsahem tuků * škodlivé účinky MeSH
- hypercholesterolemie * farmakoterapie metabolismus MeSH
- hypolipidemika farmakologie terapeutické užití MeSH
- játra metabolismus účinky léků MeSH
- konstitutivní androstanový receptor * MeSH
- lidé MeSH
- metabolismus lipidů účinky léků MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- pregnanový X receptor * metabolismus genetika MeSH
- pyridiny MeSH
- receptory cytoplazmatické a nukleární * metabolismus agonisté genetika MeSH
- regulace genové exprese účinky léků MeSH
- žlučové kyseliny a soli * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
1st Faculty of Medicine Charles University Prague Czech Republic
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
Military Faculty of Medicine University of Defence Hradec Králové Czech Republic
PamGene 's Hertogenbosch The Netherlands
School of Pharmacy Faculty of Health Sciences University of Eastern Finland Kuopio Finland
Citace poskytuje Crossref.org
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- $a The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model / $c J. Dusek, I. Mejdrová, K. Dohnalová, T. Smutny, K. Chalupsky, M. Krutakova, J. Skoda, A. Rashidian, I. Pavkova, K. Škach, J. Hricová, M. Chocholouskova, L. Smutna, R. Kamaraj, M. Hroch, M. Leníček, S. Mičuda, D. Pijnenburg, R. van Beuningen, M. Holčapek, L. Vítek, M. Ingelman-Sundberg, O. Burk, T. Kronenberger, R. Nencka, P. Pavek
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