論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 |