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Regulation of the expression of adipocytokines and a novel therapeutic strategy for a metabolic syndrome

脂肪细胞因子表达的调节和代谢综合征的新治疗策略

基本信息

批准号：
15081209
负责人：
KOMURO Ryutaro
金额：
$ 71.62万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2007
项目状态：
已结题

项目摘要

Analysis of adiponectin promoter: We found an important element for the expression of adiponectin in the upstream from the initiation codon. We also found that Glimepiride could function as a direct ligand to PPAR_γ and increase the expression of adiponectin mRNA at transcriptional level. We cloned 11kb human adiponectin promoter which was more specific to adipocyte as compared to aP2 promoter.Fat-derived reactive oxygen species (ROS): We found the upregulated gene expression of the enzymes involved in generating ROS and the downregulated gene expression of the enzymes involved in remov ing ROS in obese adipose tissue. Consequently, systemic ROS increased, adiponectin expression decreased, and the mRNA expression of proinflammatory cytokines increased. We also found that visceral fat accumulation in human were closely associated with systemic ROS level. We identified PPAR_γ-responsive element in the promoter of Catalase which we found important for obese adipose tissue.Fat hypoxia: We found that obese adipose tissue was at hypoxic state with hypoperfusion of blood and ER stress was induced in adipocytes. Consequently, the expression of CHOP mRNA increased and the adiponectin mRNA expression was reduced at transcriptional level.Fat Rho GTPases: The inhibition of RhoA-ROCK signaling pathway, which was crucial for physiologic al function of adipocyte and adipose tissue, increased the expression of adiponectin mRNA at transcriptional level.Fat-derived NO: We found the increase of the expression of NO synthase mRNA and nitrosylated protein in obese adipose tissue. We also found that NO was involved in the regulation of adiponectin expression irrespectively of JNK or NFκB signaling pathway.

脂联素启动子分析：我们在起始密码子的上游发现了脂联素表达的一个重要元件。我们还发现，格列美脲可以作为PPAR_γ的直接配基，在转录水平上增加脂联素的表达。我们克隆了11kb的人脂联素启动子，与aP2启动子相比，该启动子更具脂肪细胞特异性。脂源性活性氧物种(ROS)：我们发现肥胖脂肪组织中参与产生ROS的酶的基因表达上调，而参与清除ROS的酶的基因表达下调。结果，全身ROS增加，脂联素表达减少，促炎症细胞因子的mRNA表达增加。我们还发现人体内脏脂肪堆积与全身ROS水平密切相关。我们在过氧化氢酶启动子中发现了PPAR_γ反应元件，我们发现该元件对肥胖脂肪组织非常重要。脂肪缺氧：我们发现肥胖脂肪组织处于低氧状态，血液低灌流，脂肪细胞产生内质网应激。脂肪Rho GTP酶：抑制对脂肪细胞和脂肪组织的生理功能至关重要的RhoA-ROCK信号通路，在转录水平增加脂联素mRNA的表达。脂源性NO：我们发现肥胖脂肪组织中NO合成酶mRNA和硝酸化蛋白的表达增加。我们还发现，NO参与了脂联素表达的调节，而不是通过JNK或NFκB信号通路。