FGF21-Nrf2-ARE信号轴抑制炎症反应改善高脂诱导肝脂肪变的作用机制研究

As a new found endocrine factor, fibroblast growth factor 21 (FGF21) could protect non-alcohol fatty liver disease (NAFLD). Nuclear transcription factor-Nrf2, a key protein in cellular oxidative stress, alleviate the pathogenesis of NAFLD. However, whether FGF21 inhibit the pathogenesis of NAFLD through regulation of the transcriptional activity of Nrf2-ARE remains unknown. Our previous studies found that: 1) FGF21 protects against atherosclerosis induced by high fat diet in FGF21 / adiponectin genes double knockout mice by reducing Inflammatory cell infiltration in vessel wall; 2) high fat diet induced much more serious NAFLD in Nrf2 gene knockout mice than wild type mice; 3) FGF21 reversed liver steatosis and inhibited inflammation reactions in wild type mice, however this effect was abrogated by Nrf2 gene knockout. Based on the previous work, we intend to further explore the mechanism of Nrf2 mediated FGF21 effect on regulating NAFLD progression, the molecular mechanism of FGF21-Nrf2-ARE signaling pathway roles on metabolic changes regulation, oxidative stress and inflammation improvement, so as to seek theoretical basis for development NAFLD target to the FGF21-Nrf2-ARE signal axis.

成纤维细胞生长因子21(FGF21)作为一种新型激素抑制非酒精性脂肪肝(NAFLD)病变发展，核转录因子Nrf2是细胞氧化应激关键蛋白可参与减缓NAFLD进程，但FGF21是否通过调节Nrf2-ARE转录活性抑制NAFLD病程变化仍不清楚。我们前期研究发现FGF21明显改善高脂诱导FGF21/ADN双基因敲除鼠动脉粥样硬化，减轻血管壁炎性细胞浸润；高脂诱导Nrf2敲除鼠NAFLD病变较对照组更为明显，FGF21能显著逆转对照组肝脂肪变但对Nrf2敲除组无明显效果，且Nrf2敲除阻断FGF21对炎症信号分子抑制作用。在前期工作基础上，我们拟进一步探讨Nrf2介导FGF21调节NAFLD病变进展的作用机制，深入研究FGF21-Nrf2-ARE信号轴调控代谢变化、氧化应激及炎症反应改善肝脂肪变的分子机理，为发展针对FGF21-Nrf2-ARE信号轴进行NAFLD靶向治疗提供理论依据。

非酒精性脂肪肝（NAFLD）是一种影响全球的最大慢性肝病之一，随着肥胖和糖尿病患者的增多，其患病率也急剧上升。成纤维细胞生长因子21(FGF21)作为一种新型激素抑制NAFLD病变发展，核转录因子Nrf2是细胞氧化应激关键蛋白可参与减缓NAFLD进程。早期有报道称Nrf2调控FGF21的表达，但近年来随着 FGF21 抗氧化和抗炎症作用研究的深入，越来越多证据提示 FGF21 发挥作用可能通过 Nrf2 介导。然而NAFLD中FGF21与Nrf2的相互调控关系仍然知之甚少，这依然是一个有待于进一步深入探索的领域。本研究我们借助动物模型即采用WT和Nrf2敲除小鼠进行高脂饮食诱导的非酒精性脂肪肝与肝原代细胞中OA处理模拟体外脂质变性相结合的方式来探索。旨在探究Nrf2敲除后对NAFLD的病变影响；探索Nrf2减缓NAFLD的潜在机制研究，并通过原代肝细胞的体外实验进一步验证。结果表明Nrf2-ko后小鼠的氧化损伤加重，下游抗氧化蛋白HO-1、NQO1表达降低；但意外的是Nrf2-ko小鼠的血脂以及肝脏脂质堆积情况少于WT小鼠。这可能是因为Nrf2-ko后FGF21的表达增加，FGF21抑制炎症和氧化应激，发挥潜在的器官损伤保护作用。此外，Nrf2-ko促进了CPT1A的表达，增强了脂肪酸氧化代谢，减少脂质堆积；Nrf2-ko还促进了小鼠褐色脂肪中产热基因UCP1的表达，增加了小鼠散热。实验结果将为开发以 FGF21 及Nrf2为靶点的抗非酒精性脂肪肝新药提供证据理论基础。