成纤维细胞生长因子21参与调控非诺贝特对肝脏脂质代谢的改善作用

目的：探讨成纤维细胞生长因子21（FGF21）介导非诺贝特对小鼠肝脏脂质代谢的调控。方法：将实验小鼠分为4组，均予高脂饮食喂养：野生型对照组（WT+HFD+CTL）、野生型非诺贝特治疗组（WT+HFD+FF）、FGF21基因敲除对照组（FGF21 KO+HFD+CTL）、FGF21基因敲除非诺贝特治疗组（FGF21KO+HFD+FF）。ELISA法检测小鼠血清的FGF21及Adiponectin含量；HE与油红O染色分别用于检测肝脏组织形态学变化和脂质堆积情况；TG和TC检测试剂盒用于检测血清TG及TC的变化；qRT-PCR检测PPARα、FGF21、肝脏胆固醇调节元件结合蛋白Srebp-2、脂质氧化、分解、转运等代谢调节基因（Acaca、Acacb ABCG5、ABCG8、Cyp7a1）、PPARγ、脂联素的mRNA表达。结果：非诺贝特处理4周能显著上调小鼠肝脏PPARα和FGF21表达水平，抑制小鼠体质量增加，下调血清异常血脂水平，减轻肝脏脂质沉积状况（P ＜0.05）。非诺贝特引发的保护作用在FGF21基因缺失后出现一定程度的减弱。HE和油红O染色结果显示，敲除FGF21基因减弱非诺贝特对高脂饮食喂养小鼠肝脏脂质堆积的改善作用。在分子机制方面，非诺贝特处理能显著上调脂质氧化、分解、转运等代谢调节基因（Acacb、ABCG5、Cyp7a1等）的表达，下调Srebp-2的表达（P ＜0.05），然而，FGF21基因缺失时，这些效应被显著抑制（P ＜0.05）。同时，FGF21基因敲除可显著抑制非诺贝特诱导的PPARγ和Adiponectin的mRNA表达上调及血清水平的Adiponectin含量升高现象（P ＜0.05）。结论：FGF21介导非诺贝特发挥抗脂肪肝病变的生物学效应。

The role of FGF21 in regulating the ameliorative effect of fenofibrate on hepatic lipid metabolism

Objective: To investigate the regulating effect of fenofibrate on liver lipid metabolism in mice mediated by fibroblast growth factor 21 (FGF21). Methods: Experimental mice were divided into four groups, all fed a high-fat diet: wild-type control group (WT+HFD+CTL), wild-type fenofibrate treatment group (WT+HFD+FF), FGF21 knockout control group (FGF21 KO+HFD+CTL), FGF21 knockout fenofibrate treatment group (FGF21 KO+HFD+FF). ELISA was used to detect FGF21 and Adiponectin in mouse serum; HE and Oil Red O staining were used to detect hepatic morphological changes and lipid accumulation in liver tissue respectively;TG and TC assay kits were used to detect changes in serum TG and TC; qRT-PCR was used to detect the mRNA expression of PPARα, FGF21, hepatic cholesterol regulatory element binding protein Srebp-2, genes regulating lipid oxidation, catabolism and transport (Acaca, Acacb, ABCG5, ABCG8, Cyp7a1), PPARγ and Adiponectin.Results: Fenofibrate treatment for 4 weeks significantly up-regulated the expression levels of PPARα and FGF21 in mice liver, inhibited the increase of body mass, down-regulated the level of abnormal serum lipids and reduced the lipid deposition in liver (P<0.05). The protective effect induced by fenofibrate was somewhat diminished by the deletion of FGF21 gene. HE and Oil Red O staining showed that the knockdown of FGF21 gene diminished the ameliorative effect of fenofibrate on hepatic lipid accumulation in HFD-fed mice. In terms of molecularmechanisms, fenofibrate treatment significantly up-regulated the expression of metabolic regulatory genes (Acacb, ABCG5, Cyp7a1, etc.) for lipid oxidation, catabolism and transport, and down-regulated the expression of Srebp-2, a hepatic cholesterol regulatory element binding protein (P<0.05). However, these effects were significantly inhibited by FGF21 gene deletion (P<0.05). Meanwhile, FGF21 knockdown significantly inhibited fenofibrate induced upregulation of PPARγ and Adiponectin mRNA expression and elevated serum levels ofAdiponectin (P<0.05). Conclusion: FGF21 mediates the biological effect of fenofibrate on anti-fatty liver lesions.