Journal
MOLECULAR ENDOCRINOLOGY
Volume 19, Issue 7, Pages 1720-1739Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2004-0427
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Funding
- NCI NIH HHS [P30 CA021765, P30 CA21765] Funding Source: Medline
- NIGMS NIH HHS [R01 GM060346-03, GM60346, U01 GM061374, U01 GM61393, R01 GM060346-04, U01 GM061393-060009, U01 GM061393, U01 GM61374, R01 GM060346] Funding Source: Medline
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The pregnane X receptor (PXR) regulates the metabolism and elimination of bile salts, steroids, and xenobiotics. The sequence of the PXR ligand-binding domain diverges extensively between different animals, suggesting interspecies differences in ligands. Of the endogenous ligands known to activate PXR, biliary bile salts vary the most across vertebrate species, ranging from 27-carbon (C-27) bile alcohol sulfates (early fish, amphibians) to C-24 bile acids (birds, mammals). Using a luciferase-based reporter assay, human PXR was activated by a wide variety of bile salts. In contrast, zebrafish PXR was activated efficiently only by cyprinol sulfate, the major zebrafish bile salt, but not by recent bile acids. Chicken, mouse, rat, and rabbit PXRs were all activated by species-specific bile acids and by early fish bile alcohol sulfates. In addition, phylogenetic analysis using maximum likelihood demonstrated evidence for nonneutral evolution of the PXR ligand-binding domain. PXR activation by bile salts has expanded from narrow specificity for C-27 bile alcohol sulfates (early fish) to a broader specificity for recent bile acids (birds, mammals). PXR specificity for bile salts has thus paralleled the increasing complexity of the bile salt synthetic pathway during vertebrate evolution, an unusual example of ligand-receptor coevolution in the nuclear hormone receptor superfamily.
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