The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

TLDR

The pregnane X receptor (PXR) is a key detoxification regulator, activated by catatoxic steroids such as PCN to induce CYP3A expression and protect against harmful chemicals. This study demonstrates that PXR is activated by lithocholic acid and its 3‑keto metabolite, regulates bile‑acid metabolism genes, and functions as a physiological sensor to lower toxic bile acid levels. The authors show that PXR activation by LCA triggers coordinated expression of genes involved in bile‑acid biosynthesis, transport, and metabolism, establishing PXR as a sensor‑mediated regulator. Activation of PXR protects against LCA‑induced liver damage and indicates that PXR agonists could treat cholestatic liver disease.

Abstract

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbonitrile (PCN), which induce cytochrome P450 3A ( CYP3A ) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7α-hydroxylase ( Cyp7a1 ) and the Na + -independent organic anion transporter 2 ( Oatp2 ). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.