7-Dehydrocholesterol metabolites produced by sterol 27-hydroxylase (CYP27A1) modulate liver X receptor activity.

Abstract

7-Dehydrocholesterol (7-DHC) is a common precursor of vitamin D3 and cholesterol. Although various oxysterols, oxygenated cholesterol derivatives, have been implicated in cellular signaling pathways, 7-DHC metabolism and potential functions of its metabolites remain poorly understood. We examined 7-DHC metabolism by various P450 enzymes and detected three metabolites produced by sterol 27-hydroxylase (CYP27A1) using high-performance liquid chromatography. Two were further identified as 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC. These 7-DHC metabolites were detected in serum of a patient with Smith-Lemli-Opitz syndrome. Luciferase reporter assays showed that 25-hydroxy-7-DHC activates liver X receptor (LXR) α, LXRβ and vitamin D receptor and that 26/27-hydroxy-7-DHC induces activation of LXRα and LXRβ, although the activities of both compounds on LXRs were weak. In a mammalian two-hybrid assay, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC induced interaction between LXRα and a coactivator fragment less efficiently than a natural LXR agonist, 22(R)-hydroxycholesterol. These 7-DHC metabolites did not oppose agonist-induced LXR activation and interacted directly to LXRα in a manner distinct from a potent agonist. These findings indicate that the 7-DHC metabolites are partial LXR activators. Interestingly, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC suppressed mRNA expression of sterol regulatory element-binding protein 1c, an LXR target gene, in HepG2 cells and HaCaT cells, while they weakly increased mRNA levels of ATP-binding cassette transporter A1, another LXR target, in HaCaT cells. Thus, 7-DHC is catabolized by CYP27A1 to metabolites that act as selective LXR modulators.

• Authors: Kaori Endo-Umeda, Kaori Yasuda, Kazuyuki Sugita, Akira Honda, Miho Ohta, Minoru Ishikawa, Yuichi Hashimoto, Toshiyuki Sakaki, Makoto Makishima
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 140 Pg. 7-16 (Mar 2014) ISSN: 1879-1220 [Electronic] England
• PMID: 24269243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 26-hydroxy-7-dehydrocholesterol
• Dehydrocholesterols
• Liver X Receptors
• NR1H3 protein, human
• Orphan Nuclear Receptors
• Receptors, Calcitriol
• Cholesterol
• 25-hydroxy-7-dehydrocholesterol
• 7-dehydrocholesterol
• CYP27A1 protein, human
• Cholestanetriol 26-Monooxygenase

Topics

• Cholestanetriol 26-Monooxygenase (metabolism)
• Cholesterol (analogs & derivatives, blood, pharmacology)
• Dehydrocholesterols (metabolism)
• Humans
• Liver X Receptors
• Orphan Nuclear Receptors (drug effects, metabolism)
• Receptors, Calcitriol (drug effects)