OCT1在非酒精性脂肪肝和葡萄糖代谢中的作用

项目名称： OCT1在非酒精性脂肪肝和葡萄糖代谢中的作用

项目编号： No.81470839

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈立功

作者单位： 清华大学

项目金额： 73万元

中文摘要： 溶质载体转运蛋白构成了人体最大的膜转运蛋白家族，在药物、脂肪酸和糖等多种底物的跨膜运输中扮演着非常重要的角色。有机阳离子转运蛋白OCT1在肝脏中高度表达，也是最重要的一线抗糖尿病药物二甲双胍的转运蛋白。尽管对OCT1在药物等异源性物质的转运中进行了很多研究，但它的生理性底物和在肝脏中的药理、病理意义还亟待阐明。前期实验结果显示，OCT1基因敲除小鼠肝脏脂肪含量比对照小鼠明显降低而糖原水平却上升；代谢组学和同位素标记底物摄取实验证实硫胺素是OCT1的底物。据此，我们将利用mOct1敲除小鼠、脂肪肝模型leptin缺乏小鼠和人类hOCT1肝脏特异性转基因小鼠系统地阐述OCT1在脂肪肝和糖代谢中的作用。 本项目有望证实：1）OCT1转运生理性底物硫胺素；2）OCT1在脂肪肝发病机制中的作用，建立新型OCT1转基因脂肪肝模型；3）二甲双胍通过和硫胺素相互作用激活AMPK实现其药效。

中文关键词： 有机阳离子转运蛋白1；非酒精性脂肪肝；糖代谢；硫胺素；二甲双胍

英文摘要： Solute carriers (SLCs) comprise the largest family of membrane transporters and play vital roles of the transmembrane transport of a wide variety of substrates such as drugs, inorganic ions, amino acids, neurotransmitters, fatty acid and sugars. They are important for these endogenous or exogenous small molecules' absorption, distribution, metabolism and excretion (ADME). Organic cation transport protein 1 (OCT1/SLC22A1) belongs to the family of SLC22, specifically highly expressed in the liver. OCT1 is responsible for transporting the first line anti-diabetic drug metformin into cells. Although there are many studies focus on the drug transport activity about OCT1, but its endogenous substrates and function in liver physiology is unknown. The preliminary results based on mOct1 gene knock-out mice showed liver fat amount is significantly lower than the wild type mice but glycogen level is increased. Incidence of non-alcoholic fatty liver disease (NAFLD) in adults is about 30% and continues to rise,especially in China, but without an effective therapeutic drugs. In this research proposal, we will use the stably expressing OCT1 cell models, metabolomics and radioactive isotope-labeled substrate uptake, mouse mOct1 knockout mice and human hOCT1 liver-specific expressed transgenic mice systematically to study the endogenous substrates of OCT1, the role in liver lipid and glucose metabolism. The objectives of this study is expected to identify: 1. The endogenous substrates of OCT1 in liver; 2. The role of OCT1 in regulating fatty liver and its underlying molecular mechanisms, establish novel hOCT1 transgenic fatty liver mouse model; 3. Interaction of metformin and OCT1 endogenous substrate resulting in its activation of AMPK for its pharmacological effects.

英文关键词： OCT1;Non-Alcoholic Fatty Liver Disease;Glucose Metabolism;Thiamine;Metformin