黄连素通过调控肝脏HNF-4α/miR122通路纠正糖尿病糖脂代谢紊乱机制研究

项目名称： 黄连素通过调控肝脏HNF-4α/miR122通路纠正糖尿病糖脂代谢紊乱机制研究

项目编号： No.81200598

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 张明

作者单位： 吉林大学

项目金额： 23万元

中文摘要： 改善糖脂代谢紊乱是治疗糖尿病及其并发症的关键措施。黄连素纠正糖尿病糖脂代谢紊乱已确切，但其作用机制，以及对糖脂代谢的调节作用是否存在串话通路至今尚未清楚。最新研究表明miR122作为肝脏特异性microRNA，受到核因子HNF4α的调控，与糖脂代谢密切相关。课题组前期工作首次证明，黄连素可进入肝细胞核，抑制核因子HNF4α,PGC-1, FOXO1的表达，具有降血脂及抑制糖异生作用。本课题拟在此基础上，在高脂联合STZ诱导小鼠模型及其原代肝细胞培养上，以HNF-4α/miR122为靶点，通过对HNF-4α基因过表达或沉默联合miR122沉默及过表达干预，探讨黄连素对糖异生关键酶（PEPCK/G6Pase），脂质合成及代谢关键蛋白（SREBP-1/FAS/ACC-1/CPT-1）调控作用，揭示黄连素治疗糖尿病的直接作用靶点，阐明黄连素逆转糖尿病糖脂代谢紊乱串话通路，为其临床应用提供理论依据。

中文关键词： 2型糖尿病；黄连素；肝核转录因子；脂质代谢；肝糖异生

英文摘要： Improve glucose and lipid metabolism disorder is a key target for the treatment of diabetes and its complications. Berberine was been reported to correct glucose and lipid disorders, but its mechanism of this action, as well as whether there is a crosslink pathway existed in the regulation of glucose and lipid metabolism has not yet been clear. The latest research shows that miR122 as a liver-specific microRNA, subject to the regulation of nuclear factor HNF4α, closely related to the glucose and lipid metabolism. Our preliminary work for the first time proved that berberine can enter the liver cell nucleus, inhibition of nuclear factor HNF4α, PGC-1 of FOXO1 expression, inhibit gluconeogenesis. The present study based on our preliminary work, develope high fat diet combined STZ injection induced type 2 diabetes mice and culture its primary liver cell, target by HNF-4α gene over-expression or silencing joint with the miR122 silence and overexpression, observed the alteration of key enzyme (PEPCK/G6Pase) and key protein of lipid synthesis and metabolism regulation protein (SREBP-1/FAS/ACC-1/CPT-1), reveal the berberine in the treatment of diabetes the target of a direct role to clarify the berberine reversed the glucose and lipid disorders crosstalk pathway for its clinical application to provide a theoretical.

英文关键词： type 2 diabetes；Berberine；HNF-4a；lipid metabolism；gluconeogenesis