Identification of RXR antagonists and characterization of potent stimulation of ST 13 preadipocyte differentiation

RXR 拮抗剂的鉴定和 ST 13 前脂肪细胞分化有效刺激的表征

• 批准号: 14571118
• 负责人: SATO Mayumi
• 金额: $ 1.86万
• 依托单位: Tokyo Metropolitan Organization for Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571118/
• 关键词: diabetes; nuclear receptor; RXR; adipocyte; PPAR; RXR antagonist; PPARγ; 生活習慣病; アンタゴニスト

Retinoid X receptor (RXR) ligands PA451 and PA452 are RXR pan-antagonist and HX531 is RXR pan-antagonist with retinoic acid receptor (RAR) pan-antagonist. Ligand displacement assay elucidate that these RXR antagonist displaced natural ligand 9-cis-retinoic acid from recombinant RXR strongly. Two-hybrid assay in mammalian cells demonstrated that RXR antagonists inhibited ligand dependent RXR binding to coactivator SRC-1 (steroid receptor coactivator) dose dependently. These results indicate the compounds are full competitive antagonists of RXR, and the ideal antagonists are not produced until now. Although these RXR antagonists function as antagonist toward RXR : RAR heterodimer, as agonist toward RXR : PPARγ (peroxisome proliferator activated receptor). This agonism of RXR antagonists also demonstrates against endogenous RXR : PPARγ. Simultaneous treatment with RXR antagonists and PPARγ agonist enhance the transactivation of PPARγ response element (PPRE) via RXR : PPARγ and induction of ST 13 preadipocyte differentiation. A chimera PPARγ receptor (PPARγ-RARγ) was constructed which ligand-binding domain of PPARγ has been replacing RARγ. The agonistic action of these RXR antagonists on RXR : PPAR exchange to antagonistic action on RXR : PPAR-RAR chimera receptor. These results suggest that amphypathic activity appeared in these RXR antagonists is depend on the structure of ligand binding domain of heterodimer partner. This is the first report of RXR antagonist-mediated agonism of PPARγ activity.

维甲酸X受体（RXR）配体PA 451和PA 452是RXR泛拮抗剂，HX 531是RXR泛拮抗剂，具有维甲酸受体（RAR）泛拮抗剂。配体置换实验表明，这些RXR拮抗剂强烈地置换了重组RXR中的天然配体9-顺式维甲酸。在哺乳动物细胞中的双杂交试验表明，RXR拮抗剂抑制配体依赖性RXR结合辅激活剂SRC-1（类固醇受体辅激活剂）的剂量依赖性。这些结果表明，这些化合物是RXR的完全竞争性拮抗剂，迄今为止还没有产生理想的拮抗剂。尽管这些RXR拮抗剂作为RXR：RAR异源二聚体的拮抗剂，作为RXR：PPARγ（过氧化物酶体增殖物激活受体）的激动剂。RXR拮抗剂的这种激动作用也证明了对内源性RXR：PPARγ的拮抗作用。RXR拮抗剂和PPARγ激动剂同时处理可通过RXR：PPARγ增强PPARγ反应元件（PPRE）的反式激活并诱导ST 13前脂肪细胞分化。构建了一种嵌合型的过氧化物酶体增殖物激活受体γ受体（PPARγ-RARγ），该受体的配体结合结构域被RARγ取代。这些RXR拮抗剂对RXR：PPAR-RAR嵌合体受体的拮抗作用与对RXR：PPAR-RAR交换的激动作用一致。这些结果表明，这些RXR拮抗剂的两性作用依赖于异源二聚体配偶体的配体结合结构域的结构。这是首次报道RXR拮抗剂介导的PPARγ活性激动。

项目成果

Mechanism of adult primitive mesenchymal ST-13 preadipocyte differ entiation

成人原始间充质ST-13前脂肪细胞分化机制

• 发表时间: 2003
• 期刊: Endocrinology 144
• 作者: Yukiko Yajima;Mayumi Sato;Michihiro Sumida et al.
• 通讯作者: Michihiro Sumida et al.

Sato, M., Tai, T., Nunoura, Y., Yajima, Y., Kawashima, S., Tanaka: "Dehydrotrametenolic Acid Induces Preadipocyte Differentiation and Sensitizes Animal Models of Noninsulin-Dependent Diabetes Mellitus to Insulin"Biol. Pharm. Bull. 25. 81-86 (2002)

Sato, M.、Tai, T.、Nunoura, Y.、Yajima, Y.、Kawashima, S.、Tanaka：“脱氢曲美烯酸诱导前脂肪细胞分化并使非胰岛素依赖性糖尿病动物模型对胰岛素敏感”Biol。

Yajima, Y., Sato, M., Sumida, M., Kawashima, S.: "Mechanism of adult primitive mesenchymal ST-13 preadipocyte differentiation Endocrinology."Endocrinology. 144. 2559-2565 (2003)

Yajima，Y.，Sato，M.，Sumida，M.，Kawashima，S.：“成人原始间充质 ST-13 前脂肪细胞分化内分泌学的机制。”内分泌学。

Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity.

类维生素A配体对RIP140的影响：与类维生素A受体的分子相互作用和生物活性。

• DOI: 10.1021/bi020497k
• 发表时间: 2003
• 期刊: Biochemistry.
• 作者: Farooqui,Mariya;Franco,PeterJ;Thompson,Jim;Kagechika,Hiroyuki;Chandraratna,RoshanthaAS;Banaszak,Len;Wei,Li-Na
• 通讯作者: Wei,Li-Na

Amide conformational switching induced by protonation of aromatic substituent.

• DOI: 10.1021/ol034344g
• 发表时间: 2003-03
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: R. Yamasaki;Aya Tanatani;I. Azumaya;Shoichi Saito;K. Yamaguchi;H. Kagechika