Background

Previous study reports that fibroblast growth factor 21 (FGF21) could ameliorate hepatic fibrosis, but its mechanisms have not been fully investigated.

Methods and results

In this study, three models were used to investigate the mechanism by which FGF21 alleviates liver fibrosis. Hepatic fibrosis animal models were respectively induced by CCL₄ and dimethylnitrosamine. Our results demonstrated that liver index and liver function were deteriorated in both models. Hematoxylin and eosin and Masson’s staining showed that the damaged tissue architectonics were observed in the mice of both models. Treatment with FGF21 significantly ameliorated these changes. ELISA analysis showed that the serum levels of IL-1β, IL-6 and TNF-α were significantly elevated in both models. However, administration of FGF21 significantly reduced these inflammatory cytokines. Real-time PCR and Western blot analysis showed that treatment with FGF21 significantly decreased mRNA and protein expressions of collagenI, α-SMA and TGF-β. Platelet-derived growth factor-BB (PDGF-BB) stimulant was used to establish the experimental cell model in hepatic stellate cells (HSCs). Real-time PCR and Western blot analysis demonstrated that the expression of collagenI and α-SMA were significantly upregulated by this stimulant in model group. Interestingly, our results showed that mRNA and protein expressions of leptin were also significantly induced in PDGF-BB treated HSCs. Administration of FGF21 significantly reduced leptin expression in a dose dependent manner and these effects were reversed in siRNA (against β-klotho) transfected HSCs. Furthermore, the leptin signaling pathways related protein p-ERK/t-ERK, p-STAT3/STAT3 and TGF-β were significantly downregulated by FGF21 treatment in a dose dependent manner. The expressions of SOCS3 and Nrf-2 were enhanced by treatment with FGF21. The underlying mechanism may be that FGF21 regulates leptin-STAT3 axis via Nrf-2 and SOCS3 pathway in activated HSCs.

Conclusions

FGF21 ameliorates hepatic fibrosis by multiple mechanisms.

中文翻译：

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FGF21通过多种机制改善肝纤维化

背景

先前的研究报告称，成纤维细胞生长因子 21 (FGF21) 可以改善肝纤维化，但其机制尚未得到充分研究。

方法和结果

在这项研究中，三个模型被用来研究 FGF21 减轻肝纤维化的机制。_{CCL 4}分别诱导肝纤维化动物模型和二甲基亚硝胺。我们的结果表明，两种模型的肝指数和肝功能均出现恶化。苏木精和伊红和Masson's染色表明，在两种模型的小鼠中都观察到了受损的组织结构。FGF21 治疗显着改善了这些变化。ELISA分析显示，两种模型中IL-1β、IL-6和TNF-α的血清水平均显着升高。然而，FGF21 的施用显着降低了这些炎性细胞因子。实时荧光定量 PCR 和蛋白质印迹分析表明，FGF21 处理显着降低了胶原蛋白 I、α-SMA 和 TGF-β 的 mRNA 和蛋白表达。血小板衍生生长因子-BB (PDGF-BB) 刺激物用于建立肝星状细胞(HSCs) 的实验细胞模型。Real-time PCR和Western blot分析表明，该刺激物在模型组中胶原蛋白I和α-SMA的表达显着上调。有趣的是，我们的结果显示瘦素的 mRNA 和蛋白质表达在 PDGF-BB 处理的 HSC 中也显着诱导。FGF21 的施用以剂量依赖性方式显着降低瘦素表达，并且这些作用在 siRNA（针对 β-klotho）转染的 HSC 中被逆转。此外，瘦素信号通路相关蛋白 p-ERK/t-ERK、p-STAT3/STAT3 和 TGF-β 在 FGF21 处理下以剂量依赖性方式显着下调。FGF21处理增强了SOCS3和Nrf-2的表达。潜在机制可能是 FGF21 通过 Nrf-2 和 SOCS3 通路在活化的 HSC 中调节瘦素-STAT3 轴。

结论

FGF21 通过多种机制改善肝纤维化。