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

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, and explore whether BBR could inhibit the activity or expression of histone deacetylase and promote the histone acetylation of FGF21 gene promoter, so that BBR could elevate FGF21 expression and improve glucose and lipid metabolism.

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。

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。我课题组前期应用小檗碱（BBR）治疗非酒精性脂肪性肝病(NAFLD)患者，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 可上调FGF21，但具体机制不明。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机制上调FGF21。.本研究采用PA诱导建立脂肪肝细胞模型，高脂饮食喂养建立脂肪肝啮齿类动物模型，同时予以小檗碱干预，在细胞、组织和动物水平，验证了脂肪肝时FGF21表达上调，采用小檗碱治疗，FGF21表达进一步上调，抑制FGF21表达小檗碱改善脂肪肝的作用减弱，故表明小檗碱通过上调FGF21改善脂肪肝。小檗碱上调FGF21的作用类似去乙酰化酶抑制剂，提示小檗碱上调FGF21的机制与乙酰化调控有关，具体调控机制需要进一步研究。