Effect of CBP/p300 and SRC-1 to PPAR, LXR, FXR

CBP/p300 和 SRC-1 对 PPAR、LXR、FXR 的影响

• 批准号: 14571108
• 负责人: INOUE Ikuo
• 金额: $ 1.47万
• 依托单位: Saitama Medical School
• 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571108/
• 关键词: peroxisome proliferator-activated receptor α(PPARα); PPARγ; CREB-binding protein(CBP; p300); sterol regulatory element-binding protein-1(SREBP-1); coactivator-dependent receptor ligand interaction assay; PPAR; SREBP; liver X receptor(LXR); FXR(Fa

We used a coactivator-dependent receptor ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether or not the hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARα,δ, and γ). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays.We found that bezafibrate was a ligand for PPARα in the CARLA, and that bezafibrate induced transcriptional activation of PPARα/RXRα. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin and fluvastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARα/RXRα. Moreover, cerivastatin and fluvastatin synergistically and dose-dependently increased the transcriptional activation of PPARα/RXRα induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARα/RXRα was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreases the transactivation of NF-κB.

我们使用了辅激活因子依赖性受体配体相互作用试验（CARLA），这是一种半功能性体外试验，以确定降血脂药物是否是三种过氧化物酶体增殖物激活受体同种型（PPARα、δ和γ）的配体。我们还通过瞬时转染实验检测了这三种亚型的转录活性，发现苯扎贝特是CARLA中PPARα的配体，并且苯扎贝特诱导了PPARα/RXRα的转录激活。虽然3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂西立伐他汀和氟伐他汀不是CARLA中这三种核受体的配体，但它们诱导了PPARα/RXRα的转录激活。此外，西立伐他汀和氟伐他汀协同并呈剂量依赖性地增加苯扎贝特诱导的PPARα/RXRα的转录激活。此外，通过加入甲羟戊酸、法尼醇、香叶基香叶醇或胆固醇以及通过与固醇调节元件结合蛋白-1（SREBP-1）共转染，西伐他汀诱导的PPARα/RXRα转录激活降低。此外，他汀类药物和贝特类药物同时给药也降低了NF-κB的反式激活。

项目成果

Incue I, Itoh F: "Fibrate and Statin Synergistically Increase the Transcriptional Activities of PPARα/RXRα and Decrease the Transactivation of NFκB."Biochem Biophys Res Commun. 290. 131-139 (2002)

Incue I，Itoh F：“贝特和他汀类药物协同增加 PPARα/RXRα 的转录活性并减少 NFκB 的反式激活。”Biochem Biophys Res Commun。290. 131-139 (2002)

Nakajima T, Matsunaga T, Kawai S, Hokari S, Inoue_I, et al.: "Characterization of the epitopes specific for a monoclonal antibody 9F5-3a and qantificati on of oxidized-HDL in human plasma."Annals of Clinical Biochemistry. (in press).

Nakajima T、Matsunaga T、Kawai S、Hokari S、Inoue_I 等人：“单克隆抗体 9F5-3a 特异性表位的表征以及人血浆中氧化 HDL 的定量。”《临床生物化学年鉴》。

Inoue I, Hayashi K, Yagasaki F, et al.: "Apoptosis of endothelial cells may be mediated by genes of peroxisome proliferator-activated receptor γ1(PPARγ1)and PPARα"J Atheroscler Thromb. 10. 99-108 (2003)

Inoue I、Hayashi K、Yagasaki F 等人：“内皮细胞凋亡可能由过氧化物酶体增殖物激活受体 γ1 (PPARγ1) 和 PPARα 的基因介导”J Atheroscler Thromb. 10. 99-108 (2003)。

Inoue_I, Katayama S.: "The possible of actions of drugs : PPARα agonist, PPARγ agonist, A HMG-CoA reductase inhibitor, ACE inhibitor, or Ca-antagonist on vascular endothelial cells as therapeutic targets"Current drug target cardiovascular and hematologica

Inoue_I，Katayama S.：“药物作用的可能性：PPARα激动剂、PPARγ激动剂、HMG-CoA还原酶抑制剂、ACE抑制剂或Ca拮抗剂对血管内皮细胞作为治疗靶点”当前药物针对心血管和血液学

Nagasaka H, Kikuta H, Chiba H, Murano T, Harashima H, Ohtake A, Senzaki H, Sasaki N, Inoue I: "Two cases with transient lipoprotein lipase (LPL) activity impairment : evidence for the possible involvement of an LPL inhibitor."Eur J Pediatr. 162. 132-138 (

Nagasaka H、Kikuta H、Chiba H、Murano T、Harashima H、Ohtake A、Senzaki H、Sasaki N、Inoue I：“两例短暂性脂蛋白脂肪酶 (LPL) 活性受损：证据可能涉及 LPL 抑制剂。