Authors
Valérie Brousseau, Eva Rettenmeier, Mélanie Verreault, Jocelyn Trottier, Shujuan Chen, Robert H Tukey, Olivier Barbier
Published in
Scientific reports. Jul 13, 2026. Epub Jul 13, 2026.
Abstract
24S-hydroxycholesterol (24SOH-Chol) is a bioactive cholesterol metabolite formed in the brain. This endogenous activator of the cholesterol sensor, liver X receptor (LXR) is abundantly found as a sulfate-glucuronide diconjugate in the human plasma. The present study characterizes the human sulfonating (SULT) and glucuronidating (UGT) enzymes; and evaluates how these enzymes impact its ability to bind to and activate LXR. In vitro enzymatic assays identified the human SULT2A1 and UGT1A4 as the major isoforms for hepatic 24SOH-Chol sulfonation and glucuronidation, respectively. Additional assays demonstrated that 24SOH-Chol-3Sulfate,24Glucuronide formation requires the successive involvement of UGT1A4 and SULT2A1. TR-FRET and transient transfection experiments revealed that glucuronidation, but not sulfonation, inactivates 24SOH-Chol. Exposure of human liver cells and humanized UGT1 mice to LXR ligands identified UGT1A4, but not SULT2A1, as a positively regulated LXR target gene, while chromatin immunoprecipitation assays, luciferase reporter and siRNA knock down assays demonstrated the ability of LXR to bind to and activate the human UGT1A4 gene promoter. The present study establishes the complementary roles played by SULT2A1 and UGT1A4 in 24SOH-Chol conjugation. We also identify glucuronidation as a mechanism allowing this cholesterol derivative to self-stimulate its own inactivation.
PMID:
42443275
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.
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