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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00616504" target="_blank" >RIV/61388963:_____/25:00616504 - isvavai.cz</a>
Alternative codes found
RIV/68378050:_____/25:00616504 RIV/00216208:11160/25:10496116 RIV/60162694:G44__/26:00564524 RIV/00216208:11150/25:10496116 and 2 more
Result on the web
<a href="https://doi.org/10.1038/s41467-025-56642-y" target="_blank" >https://doi.org/10.1038/s41467-025-56642-y</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41467-025-56642-y" target="_blank" >10.1038/s41467-025-56642-y</a>

Result language
angličtina
Original language name
The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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