| RRC ID |
44761
|
| 著者 |
Endo-Umeda K, Yasuda K, Sugita K, Honda A, Ohta M, Ishikawa M, Hashimoto Y, Sakaki T, Makishima M.
|
| タイトル |
7-Dehydrocholesterol metabolites produced by sterol 27-hydroxylase (CYP27A1) modulate liver X receptor activity.
|
| ジャーナル |
J Steroid Biochem Mol Biol
|
| 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.
|
| 巻・号 |
140
|
| ページ |
7-16
|
| 公開日 |
2014-3-1
|
| DOI |
10.1016/j.jsbmb.2013.11.010
|
| PII |
S0960-0760(13)00264-1
|
| PMID |
24269243
|
| MeSH |
Cholestanetriol 26-Monooxygenase / metabolism*
Cholesterol / analogs & derivatives
Cholesterol / blood
Cholesterol / pharmacology
Dehydrocholesterols / metabolism*
Humans
Liver X Receptors
Orphan Nuclear Receptors / drug effects*
Orphan Nuclear Receptors / metabolism
Receptors, Calcitriol / drug effects
|
| IF |
3.813
|
| 引用数 |
14
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2 |
