Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver

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 (<i>Akr1b7</i>), 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 <i>Orm1</i> and <i>Orm2</i> expressions were completely abolished in the absence of both CAR and PXR following CA feeding. In addition, we found that <i>Orm</i> 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.<b>NEW & NOTEWORTHY</b> Hepatic bile acid signaling plays a crucial role in coordinating systemic metabolism between the liver and other peripheral tissues. Our report demonstrates that, under bile acid-enriched conditions, activation of nuclear receptors CAR and PXR stimulate the expression of several putative hepatokines, including the orosomucoid gene family, which may exert regulatory effects in the liver and adipose tissue against metabolic disorders.