College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China.
College of Pharmacy, Guilin Medical University, Guilin, 541004, PR China.
Chem Biol Interact. 2019 Feb 1;299:131-139. doi: 10.1016/j.cbi.2018.12.006. Epub 2018 Dec 11.
Liver fibrosis is a pathological wound-healing response caused by chronic liver damage due to a virus, autoimmune disorder, or drugs. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Methyl ferulic acid (MFA), a biologically active monomer, has a protective effect on liver injury. However, the effects and roles of MFA in liver fibrosis remain unknown. The purpose of the current study was to investigate the effect of MFA on hepatic fibrosis and the underlying mechanisms. Human hepatic stellate LX-2 cells were exposed to 5 μg/L TGF-β1 for 48 h to stimulate liver fibrosis in vitro. Using MTT, RT-PCR and Western blot analysis, we revealed that MFA significantly inhibited the proliferation of LX-2 cells as well as decreased the expressions of α-SMA and type I collagen in LX-2 cells. SD rats were fed with ethanol, and this combined with the intraperitoneal injection of CCl induced liver fibrosis in vivo. We found that the administration of MFA markedly decreased the levels of hyaluronic acid (HA), procollagen type III (PC-III), type IV collagen (CIV) and laminin (LN) in the serum, inhibited the expression of α-smooth muscle actin (α-SMA) as well as type I and type III collagen, and up-regulated the ratio of MMP-2/TIMP-1 in rats. The antifibrotic effects of MFA were also evaluated by H&E staining and Masson's trichrome staining. In addition, further studies suggested that this protection by MFA from liver fibrosis was possibly related to the inhibition of TGF-β1/Smad and NOX4/ROS signalling. In conclusion, our results demonstrate that MFA attenuated liver fibrosis and hepatic stellate cell activation by inhibiting the TGF-β1/Smad and NOX4/ROS signalling pathways.
肝纤维化是一种由病毒、自身免疫性疾病或药物引起的慢性肝损伤导致的病理性伤口愈合反应。肝星状细胞（HSCs）在肝纤维化的发病机制中起着至关重要的作用。甲基阿魏酸（MFA）是一种具有生物活性的单体，对肝损伤具有保护作用。然而，MFA 对肝纤维化的作用和作用机制尚不清楚。本研究旨在探讨 MFA 对肝纤维化的影响及其潜在机制。体外将人肝星状细胞 LX-2 用 5μg/L TGF-β1 孵育 48h 以刺激肝纤维化。通过 MTT、RT-PCR 和 Western blot 分析，我们发现 MFA 显著抑制 LX-2 细胞的增殖，同时降低 LX-2 细胞中α-SMA 和 I 型胶原的表达。SD 大鼠给予乙醇喂养，并联合腹腔注射 CCl 诱导体内肝纤维化。我们发现，MFA 给药显著降低了血清中透明质酸（HA）、III 型前胶原（PC-III）、IV 型胶原（CIV）和层粘连蛋白（LN）的水平，抑制了α-平滑肌肌动蛋白（α-SMA）以及 I 型和 III 型胶原的表达，并上调了大鼠 MMP-2/TIMP-1 的比值。通过 H&E 染色和 Masson 三色染色评估 MFA 的抗纤维化作用。此外，进一步的研究表明，MFA 对肝纤维化的保护作用可能与抑制 TGF-β1/Smad 和 NOX4/ROS 信号通路有关。总之，我们的研究结果表明，MFA 通过抑制 TGF-β1/Smad 和 NOX4/ROS 信号通路减轻肝纤维化和肝星状细胞激活。
