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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-02-06 DOI:10.1038/s41467-025-56642-y

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

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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.

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CAR激动剂/ PXR拮抗剂联合MI-883在饮食诱导的高胆固醇血症模型中的降血脂作用

组成型雄甾烷受体（CAR）和孕烷X受体（PXR）是密切相关的核受体，在外源清除中具有重叠的调节功能，但在内源性代谢中具有不同的作用。Car激活已被证明通过调节胆固醇代谢和胆汁酸消除来改善高胆固醇血症，而PXR激活与高胆固醇血症和肝脏脂肪变性有关。在这里，我们展示了一种人类CAR激动剂/PXR拮抗剂MI-883，它通过利用CAR和PXR在基因调控中的相互作用，有效地调节与外源代谢和胆固醇/胆汁酸稳态相关的基因。通过脂质组学、胆汁酸代谢组学和转录组学对饲喂高脂高胆固醇饲料的人源化PXR-CAR-CYP3A4/3A7小鼠进行综合分析，我们发现MI-883能显著降低血浆胆固醇水平，促进粪便胆汁酸排泄。这项工作为开发针对多种外源核受体的配体铺平了道路。这种配体具有精确调节肝脏代谢的潜力，为代谢紊乱提供了新的治疗策略。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.