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Transcriptional repression of PAI-1 gene expression by leptin receptor signal-mediated mechanisms.

瘦素受体信号介导机制对 PAI-1 基因表达的转录抑制。

基本信息

批准号：
13670209
负责人：
IHARA Hayato
金额：
$ 0.9万
依托单位：
HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670209/
关键词：
Leptin Leptin receptor PAI-1 Adipocytes obese mice 3T3-L1細胞遺伝的肥満マウスob ob

项目摘要

Obese patients are at risk for development of cardiovascular disease, which can in part be explained by disturbances in the haemostatic and fibrinolytic systems. Recently, it has been demonstrated that the adipocyte itself is able to produce a primary fibrinolytic inhibitor, PAI-1, possibly accounting for the elevated PAI-1 levels in obesity. We hypothesized that leptin receptor signal transduction pathway might regulate PAI-1 gene expression in adipocytes, which could be activated by leptin secreted from these cells. Administration of recombinant leptin to ob/ob genetic obese mice not only caused reduction of plasma levels of PAI-1 but also repression of PAI-1 gene expression in abdominal fat, subcutaneous fat tissues, and lung tissue after 6 hr and 24 hr treatments. Cotransfection of 3T3-L1 preadipocyte with 5-PAI-1/Luc reporter and leptin expression vectors revealed that PAI-1 promoter activities were repressed in a dose-dependent manner. These results suggested that exogenous addition of leptin caused repression of PAI-1 expression in vivo and in vitro. Adipocytes express at least two kinds of leptin receptors ; long-and short-form. To identify the leptin receptor (LepR) involved in repression of PAI-1 gene expression, 3T3-L1 preadipocyte were transfected with leptin, and either short-or long-form LepR expression vectors, and then luciferase activities were measured after 48-hr incubation. Transfection in combination with leptin and short-form LepR expression vectors reduced PAI-1 gene transcriptional activities to 70〜75% of control value, while the transcriptional activities were up-regulated 1.8〜2 fold by transfection with leptin and long-form LepR expression vectors. These results suggested that decreased PAI-1 gene expression by leptin treatment was due to the short-form LepR signaling-mediated mechanisms.

肥胖患者有患心血管疾病的风险，部分原因是止血和纤溶系统紊乱。最近，已经证明脂肪细胞本身能够产生主要纤溶抑制剂 PAI-1，这可能是肥胖患者 PAI-1 水平升高的原因。我们推测瘦素受体信号转导通路可能调节脂肪细胞中PAI-1基因的表达，而脂肪细胞分泌的瘦素可以激活PAI-1基因的表达。对ob/ob遗传性肥胖小鼠施用重组瘦素不仅导致血浆PAI-1水平降低，而且在治疗6小时和24小时后，腹部脂肪、皮下脂肪组织和肺组织中的PAI-1基因表达受到抑制。 3T3-L1 前脂肪细胞与 5-PAI-1/Luc 报告基因和瘦素表达载体的共转染表明，PAI-1 启动子活性以剂量依赖性方式受到抑制。这些结果表明，外源添加瘦素导致体内和体外 PAI-1 表达的抑制。脂肪细胞表达至少两种瘦素受体；长形式和短形式。为了鉴定参与抑制 PAI-1 基因表达的瘦素受体 (LepR)，用瘦素以及短或长形式的 LepR 表达载体转染 3T3-L1 前脂肪细胞，然后在孵育 48 小时后测量荧光素酶活性。联合转染瘦素和短型LepR表达载体使PAI-1基因转录活性降低至对照值的70〜75%，而转染瘦素和长型LepR表达载体则转录活性上调1.8〜2倍。这些结果表明，瘦素治疗降低 PAI-1 基因表达是由于短形式 LepR 信号介导的机制。