硫氧还蛋白及其还原酶通过胰岛素/脂联素信号通路参与胰岛素抵抗的机制研究

项目名称： 硫氧还蛋白及其还原酶通过胰岛素/脂联素信号通路参与胰岛素抵抗的机制研究

项目编号： No.31470790

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 钟良玮

作者单位： 中国科学院大学

项目金额： 80万元

中文摘要： 胰岛素抵抗是2型糖尿病的主要特征，严重威胁着人类健康，其发病机制急需深入研究。我们发现，硫氧还蛋白（Trx）及其还原酶（TrxR）活性，在胰岛素抵抗小鼠血清中增高，在肝脏中降低可脂酰化程度增高；人血清中Trx与脂联素相结合。于是思索：Trx/TrxR具有促二硫键还原的能力，而调控糖脂代谢的胰岛素及其受体、高分子量脂联素需二硫键维持结构与功能；血清Trx/TrxR活性异常增高，很可能会干扰胰岛素/脂联素信号通路，导致肝内游离脂肪酸积累，修饰和抑制Trx/TrxR，促进氧化应激。为此拟研究：（1）人血清中Trx/TrxR活性与2型糖尿病、胰岛素、高分子量脂联素含量的相关性；（2）细胞外液中Trx/TrxR对胰岛素/脂联素与肝细胞膜相应受体结合、激活下游经典蛋白的影响；（3）Trx/TrxR与脂联素互作的分子机制；（4）软脂酸抑制Trx/TrxR的机制及修饰位点。以期为2型糖尿病防治提供新思路。

中文关键词： 硫氧还蛋白还原酶；蛋白互作；胰岛素抵抗；S-软脂酰化；脂联素

英文摘要： Insulin resistance, a major characteristic feature of type 2 diabetes, has been bringing many serious health problems to a large amount of people. It is thus important to further clarify the mechanism underlying the development of insulin resistance. We found that thioredoxin (Trx)/thioredoxin reductase (TrxR) activities elevated in the sera of insulin-resistant mice, which however contained the reduction of hepatic Trx/TrxR activities in parallel with increased degree of palmitoylated Trx/TrxR. In addition, Trx was found to interact with adiponectin in human serum. In view of the ability for Trx/TrxR to catalyze the reduction of disulfide bond, the latter is critical to maintaining insulin, insulin receptor and high-molecular-weight adiponectin structure and functions, we thus speculated that the increased Trx/TrxR in serum would affect hepatic sugar and lipid metabolisms via insulin and adiponectin signaling pathways, leading to increased levels of free fatty acids, which may modify and inhibit Trx/TrxR. To confirm our speculation, we are planning to study: (1) the relationship among human serum Trx/TrxR activity, type 2 diabetes, the levels of serum insulin and high-molecular-weight adiponectin; (2) the effects of extracellular Trx/TrxR on insulin/adiponectin binding to corresponding receptors, and activating classic downstream proteins; (3) the mechanism underlying the interaction between Trx/TrxR and adiponectin; (4) the molecular mechanism and modification site(s) behind the inhibition of Trx/TrxR by palmitate. Our results are expected to provide new insights into the prevention and treatment of insulin resistance.

英文关键词： Thioredoxin reductase;Interaction between proteins;Insulin resistance;S-palmitoylation;Adiponectin