血红素对胰岛素敏感性的调控作用和分子机制研究

Insulin resistance is a major feature of type 2 diabetes. It has been reported that the uptake of heme is positively correlated with type 2 diabetes, but the effect of heme on insulin sensitivity and the underlying mechanisms are still unclear. Heme is an important cofactor for oxygen transport, respiratory electron transport and so on, and is also a sensor of gases such as oxygen. Recently, heme has been shown to reversibly bind with some proteins to regulate their biological functions. In this study, first, we will investigate whether heme can induce insulin resistance at cellular and animal levels. Second, we will analyze and screen potential heme binding proteins from proteins correlated with insulin sensitivity, according to the feature of heme binding motif and the binding assay for heme and the synthetic peptides. Subsequently, for the validated peptides, the corresponding proteins will be expressed and purified from prokaryotic and eukaryotic systems, and their binding with heme will be confirmed by specific light absorption and LC/MS. Then, the effect of heme on these heme binding proteins and the underlying molecular mechanisms will be investigated. Finally, the heme binding proteins will be overexpressed or knocked down by siRNA to investigate whether a specific heme binding protein mediates the effect of heme on insulin sensitivity at both cellular and animal levels. If this project can be approved, we will elucidate the effect of heme on insulin sensitivity and the related molecular mechanisms, which will provide new clues for preventing and treating insulin resistance related diseases.

胰岛素抵抗是2型糖尿病的主要特征。人群研究显示血红素摄入量与胰岛素抵抗和2型糖尿病呈正相关，但血红素对胰岛素敏感性的调控作用和机制还不太清楚。血红素可作为蛋白的辅因子参与运载氧、传递电子等并可感应氧气等气体。最近研究发现血红素还可与蛋白可逆结合而调控其生物学功能。本项目拟首先在细胞和小鼠水平研究血红素对胰岛素抵抗的诱导作用。其次，根据氨基酸序列特征和多肽与血红素的结合实验，分析和筛选可能与血红素结合的胰岛素敏感性调控蛋白。接着，通过原核和真核表达纯化候选蛋白并进行比色和质谱分析等，验证与血红素的结合。对于找到的血红素结合蛋白，研究血红素对其调控作用并探索相关分子机制。最后，在细胞和动物水平，通过过表达或siRNA调节蛋白水平，研究血红素诱导的胰岛素抵抗是否由某个特定的血红素结合蛋白所介导。本项目的开展将揭示血红素对胰岛素抵抗的诱导作用和相关分子机制，为胰岛素抵抗相关疾病的防治提供新的思路。

胰岛素抵抗是2型糖尿病的主要特征，但血红素对胰岛素敏感性的调控作用和机制还不太清楚。本项目以原代肝细胞和小鼠作为研究模型，发现在胰岛素抵抗的情况下，高铁血红素能改善原代肝细胞胰岛素信号转导，包括增强胰岛素信号通路关键蛋白的磷酸化和胰岛素刺激的FoxO1的出核转运，提示高铁血红蛋白可以改善胰岛素敏感性。此外，高铁血红素能减少棕榈酸诱导的原代肝细胞甘油三酯和游离脂肪酸的积累。在高脂诱导小鼠的食物中添加高铁血红素能降低小鼠体重、空腹血糖和甘油三酯水平，减少能量摄入，改善胰岛素耐受和葡萄糖耐受以及肝脏胰岛素敏感性和肝脏脂肪变性。进一步研究发现高铁血红素处理后能下调小鼠肝脏中脂肪合成调控、脂肪酸摄入和储存的关键基因的mRNA和蛋白水平，同时上调脂肪酸氧化关键基因的mRNA水平和CPT1的酶活力水平。本项目的研究结果为胰岛素抵抗相关脂代谢疾病的防治提供了新的思路。本项目自立项以来，共发表研究论文6篇，其中有1篇论文获得专评。总体上较好地完成了本项目。

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