小檗碱通过调控成纤维细胞生长因子21的表达改善脂肪肝的机制研究

项目名称： 小檗碱通过调控成纤维细胞生长因子21的表达改善脂肪肝的机制研究

项目编号： No.81200627

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： 颜红梅

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 成纤维细胞生长因子21（FGF21）具有降糖、降脂、减轻肝脂肪含量等作用，但需注射给药且半衰期短限制了其直接临床应用，可上调FGF21的药物是治疗代谢异常疾病的新选择。我课题组前期研究显示，非酒精性脂肪性肝病(NAFLD)患者经小檗碱（BBR）治疗后，血糖、血脂、脂肪肝等代谢异常显著改善，同时伴有血清FGF21升高，提示BBR对FGF21有调控作用（上调），但具体机制不明。已知FGF21受小分子物质（丁酸钠）的乙酰化调控，使FGF21组蛋白乙酰化增加从而激活其转录。我课题组前期研究显示BBR具有调控组蛋白乙酰化作用，推测BBR可能通过乙酰化调控而上调FGF21。因此，本研究拟采用小檗碱干预脂肪变性肝细胞模型及啮齿类动物模型，在细胞、组织和动物水平，探索BBR是否通过抑制组蛋白去乙酰化酶的活性或表达、促进包绕FGF21 启动子区域组蛋白赖氨酸残基乙酰化来上调FGF21表达，发挥改善代谢作用。

中文关键词： 小檗碱（BBR）；成纤维细胞生长因子21（FGF21）；非酒精性脂肪性肝病（NAFLD)；乙酰化；

英文摘要： Fibroblast growth factor 21 (FGF21) has signifcant beneficial effects to cure hyperglycemia, hyperlipidemia and reduce hepatic fat accumulation. However, direct therapeutic use of FGF21 is seriously restricted by its short half-life in the serum, so a stable medicine that can up-regulate FGF21 expression and have a longer half-life would be ideal to treat multiple metabolic disorders. Our previous studies have shown that berberine(BBR) treatment could significantly improve glucose and lipid metabolism, and decrease hepatic fat content in non-alcoholic fatty liver disease (NAFLD) patients, and further study showed that the BBR effects on metabolic disorders were accompanied by elevation of serum FGF21, which indicate that BBR's metabolic beneficial effect might be related to its effect on FGF21 expression. However, the mechanism underlying BBR's effects on FGF21 expression is still not clear. Previously we found that BBR played an important role in regulating histone acetylation, and one recent study also showed that serum FGF21 level could be regulated by sodium butyrate in a histone-acetylation dependent way. Thus, we assumed that BBR also up-regulated the FGF21 expression through the alteration of FGF21 histone acetylation. To verify this assumption, we plan to use BBR to treat NAFLD celluar and animal models,

英文关键词： Berberine(BBR)；Fibroblast growth factor 21 (FGF21)；non-alcoholic fatty liver disease (NAFLD)；acetylation；