基于肠肝轴研究FGF21在酒精性肝病中对肠道的保护作用及其机制

Chronic alcohol consumption may cause intestinal barrier dysfunction resulting in a release of gut-derived endotoxin in the circulation, which causes liver steatosis and injury. This gut-liver axis has been recognized as one of the major mechanisms in alcoholic liver disease (ALD). Our previous studies demonstrated that fibroblast growth factor 21 (FGF21) was significantly increased by alcohol consumption and recombinant FGF21 had protective effects in experimental ALD, and global FGF21 depletion caused enhanced ALD which was associated with the alterations in gastrointestinal motility, gut microbiota, and leaky gut. However, the underlying mechanism is not clear. Our preliminary data showed that intestinal hypoxia inducible factor 1α (HIF1α) plays an important role in intestinal barrier function. Intestinal specific HIF-1a knockout resulted in an exacerbated liver steatosis and injury. We thus hypothesize that the protective effect of FGF21 against ALD is mediated by intestinal epithelial HIF-1α upregulation that enhances intestinal barrier and reduces endotoxin release. To test this hypothesis, we proposed this project and designed following three specific aims to investigate the role of FGF21 in gut-liver axis in ALD. Aim 1 will examine the role of FGF21 in gastrointestinal motility, gut microbiota and intestinal barrier in ALD using global FGF21 overexpressing and knockout mice. Aim 2 is to determine whether FGF21 activates intestinal HIF-1a through ERK phosphorylation using intestinal epithelial specific HIF-1α KO mice. Completion of this project will gain knowledge of insights into the mechanism of the role of FGF21 in gut-liver axis and provide a foundation for FGF21-based therapy in ALD and beyond.

肠肝轴即肠道与肝脏的相互关系成为近年的研究热点。在酒精性肝病（ALD）中肠道损伤导致肠源性内毒素入血造成肝脏受损被认为是其重要的发病机制。我们前期初步研究表明具有内分泌特性的成纤维细胞生长因子21（FGF21）在ALD中对肝脏有保护作用，同时发现FGF21缺失影响胃肠道蠕动、肠道通透性和肠道菌群。另外，在ALD中我们发现肠道HIF1α缺失加重肝脏损伤，与肠道屏障受损密切相关。鉴于此，我们假设FGF21通过HIF1α介导保护ALD中的肠道损伤，减少肠源性内毒素而发挥对肝脏的保护作用。我们将以FGF21过表达、FGF21全基因敲除和肠道上皮特异性HIF1α基因敲除3种小鼠与相应对照建立ALD模型，验证FGF21在ALD中是否通过HIF1α介导保护肠道而发挥护肝作用，为基于肠肝轴防治ALD提供新理论和新策略，对研究肠道疾病也有借鉴意义。

成纤维细胞因子21主要由肝脏分泌的内分泌因子， 我们前期研究证明了FGF21可以改善酒精性肝病的肝损伤，同时也发现FGF21敲除小鼠肠道通透性增高，而肠漏是酒精性肝病(ALD)的重要发病机理，于是我们基于肠肝轴的理论推测FGF21可以改善ALD肠道损伤继而发挥肝脏的保护作用。研究内容：确定FGF21在ALD中对肠道和肝脏损伤的保护作用，探究FGF21在ALD中保护肠道损伤的机制是否通过HIF1α来介导。重要结果：明确了FGF21在ALD中对肠道和肝脏损伤的保护作用，FGF21在ALD中保护肠道损伤的机制通过HIF1α来介导。关键数据：在慢性酒精性饲养造成的ALD小鼠模型中，FGF21基因敲除小鼠肝脏肠道损伤更重，给予FGF21改善，血液中内毒素在普通酒精喂养小鼠平均为0.21EU/ml，敲除小鼠为0.52EU/ml，而给予FGF21后降为0.13EU/ml。通过体外细胞实验也验证了FGF21对Caco2肠道细胞的保护作用并在mRNA和蛋白质水平验证了Hif1a的介导作用，为FGF21治疗酒精性肝病提供了新理论新策略。