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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216275%3A25310%2F25%3A39923053" target="_blank" >RIV/00216275:25310/25:39923053 - isvavai.cz</a>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10400 - Chemical sciences

Projekt

<a href="/cs/project/EH22_008%2F0004644" target="_blank" >EH22_008/0004644: Záchrana životů prostřednictvím výzkumu v oblasti včasné detekce a prevence rakoviny: Molekulární, genomické a sociální faktory</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

NATURE COMMUNICATIONS

ISSN

—

e-ISSN

2041-1723

Svazek periodika

16

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

21

Strana od-do

1418

Kód UT WoS článku

001416001300010

EID výsledku v databázi Scopus

2-s2.0-85218266836