Children’s Nutrition Research Center Staff Publications

Language

English

Publication Date

6-1-2025

Journal

American Journal of Physiology-Endocrinology and Metabolism

DOI

10.1152/ajpendo.00417.2024

PMID

40327538

PMCID

PMC12158448

PubMedCentral® Posted Date

6-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors activated by various xenobiotics, drugs, hormones, and bile acids (BAs). Upon activation, these nuclear receptors play critical roles in regulating systemic energy homeostasis. However, precise mechanisms through which CAR and PXR influence systemic metabolism remain incompletely understood. Here, we investigated the impact of CAR and PXR on the liver-secreted hormone (i.e., hepatokine) expressions in response to BA stress such as cholic acid (CA) feeding. Our analysis revealed that several BA-activated genes, including the well-known CAR/PXR target, aldo-keto reductase family 1, member B7 (Akr1b7), were commonly increased by CAR- and PXR-agonist treatments. Notably, we identified a gene cluster encoding new BA-regulated hepatokines, orosomucoids (ORMs), as direct transcriptional targets of CAR and PXR. The Orm1 and Orm2 expressions were completely abolished in the absence of both CAR and PXR following CA feeding. Additionally, we found that Orm transcriptions are dynamically regulated under various metabolic conditions, proposing a potential contribution of CAR/PXR. In conclusion, our study demonstrated that BA stress activates CAR and PXR, which play a key role in regulating hepatokine expression, including ORMs. This suggests a potential link between hepatic BA signaling, CAR/PXR activity, and systemic metabolic effects.

Keywords

Animals, Receptors, Cytoplasmic and Nuclear, Bile Acids and Salts, Liver, Pregnane X Receptor, Constitutive Androstane Receptor, Mice, Male, Xenobiotics, Mice, Inbred C57BL, Gene Expression Regulation, Cholic Acid, bile acid, xenobiotic nuclear receptor, constitutive androstane receptor, pregnane X receptor, secretome, orosomucoid

Published Open-Access

yes

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