FGF-21通过Sirt-1途径对酒精诱导肝脏脂肪堆积改善作用的机制研究

Fibroblast growth factor (FGF)-21 is one of the cytokines recently discovered to regulate lipid and glycometabolism. Previous studies have demonstrated that FGF-21 may have therapeutic potential for the treatment of non-alcoholic fatty liver disease. Our preliminary findings show that injection of recombinant human FGF-21 in a rat model of alcoholic fatty liver disease can largely alleviate the accumulation of fat in the liver and reduce alcohol-induced liver injury. Given these promising findings, we propose to continue our research to further understand the molecular biological mechanisms for which FGF-21 may play a role in alcoholic fatty liver disease. We will explore the possible role of FGF-21 in the initiation and progression of alcohol-induced fatty liver. Earlier work has suggested that FGF-21 may play a role in alleviating fat accumulation in the liver via attenuation of the Sirt (sirtuin)-1-SREBP (sterol regulatory element binding protein)-1c/PGC (PPAR coactivator )-1a axis. Specifically we will a). confirm and extend our early findings by conducting a rigorous pharmacological investigation of a dose response of FGF-21 in the rodent model of alcoholic fatty liver disease b). investigate the biological activation and signaling of Sirt-1 and fat accumulation over a time course in hepatic cell H4IIE in vitro assays exposed to ethanol. The deliverables and results of this study will provide greater understanding of the role of FGF-21 and Sirt-1 in alcoholic fatty liver disease and may have important clinical and social significance by providing both a theoretical and tested concept as a basis for the development of new medicines aimed at curing alcoholic liver disease.

成纤维细胞生长因子21（FGF-21）是新发现的调节糖脂代谢的细胞因子。研究表明：FGF-21对非酒精性脂肪肝具有明显的治疗作用，而酒精性脂肪肝和非酒精性脂肪肝具有相同的病理变化过程。我们的前期研究结果表明，给酒精性脂肪肝小鼠注射重组人FGF-21可以显著减轻肝脏的脂肪堆积，改善酒精对肝脏的损伤。因此，我们将在此基础上继续研究FGF-21对酒精性脂肪肝改善作用的分子生物学机制，探讨FGF-21逆转酒精性肝病发展过程的可能性。根据前期工作，我们假设FGF21通过调节Sirt-1-SREBP-1c/ PGC-1α发挥降低肝脏脂肪堆积的作用。我们将给酒精性脂肪肝小鼠注射FGF21研究FGF-21的调节作用，同时利用酒精处理肝细胞系H4IIE阐明Sirt-1途径在FGF21改善酒精诱导肝脏脂肪堆积中的机制。本研究的完成，将进一步阐明FGF-21的作用，同时为开发治疗酒精性肝病的药物提供理论基础。

成纤维细胞生长因子21（FGF-21）是新发现的调节糖脂代谢的细胞因子。最新研究表明：FGF-21对非酒精性脂肪肝具有明显的治疗作用，而酒精性脂肪肝和非酒精性脂肪肝具有相同的病理变化过程。我们的研究结果表明，给酒精性肝病小鼠注射重组人FGF-21可以逆转慢性酒精饲喂引起的肝脏脂肪变性和炎症损伤。我们还发现FGF21对慢性-急性酒精性肝损伤的保护作用。同时，我们也体外培养H4ⅡE细胞，研究FGF-21发挥作用的分子调控机制。发现酒精显著诱导肝H4IIE细胞脂肪堆积，当我们同时给予5ug/ml的重组FGF21处理时，酒精诱导的脂肪堆积显著降低。此外，我们也探讨了FGF21在慢性酒精诱导脂肪肝小鼠中的作用以及作用机理。将雄性FGF21敲除（FGF21KO）和对照（WT）小鼠分别喂含有5％酒精的Lieber DeCarli饮食和等热量（对照）饮食处理4周，评估肝脂肪变性和炎症损害程度。同时，分析肝脏中参与脂肪生成和脂肪酸β-氧化的蛋白和基因水平。喂饲酒精显著增加循环和肝脏中FGF21的表达。FGF21缺失加剧了酒精诱导的肝脂肪变性和肝损伤，与参与SREBP1c介导的脂肪生成的基因的活化增强有关，同时降低了由PGC1α介导的脂肪酸β-氧化的基因的表达。这些结果表明酒精诱导的FGF21表达是脂质失调时肝脏的适应性反应。靶向FGF21信号的干预可能是酒精性脂肪性肝炎的新型治疗方法。本研究结果进一步阐明了FGF-21的生物学功能，为开发治疗酒精性肝病的药物提供理论和前期基础，具有重要的临床意义和社会价值。