Medical School of Ningbo University, Ningbo, 315211, China.
Ningbo College of Health Sciences, Ningbo, China.
Pharmacol Rep. 2020 Aug;72(4):935-944. doi: 10.1007/s43440-019-00043-8. Epub 2020 Jan 8.
Fenofibrate was reported to be beneficial for cholestasis in combination with ursodeoxycholic acid. However, its therapeutic action as single therapy for chronic cholestasis and the underlying mechanism are not known.
In the present study, wild-type (WT) mice were administered a 0.05% ANIT diet to mimic chronic cholestatic liver injury. Mice were dosed fenofibrate 25 mg/kg twice every day for 10 days to investigate the therapeutic action of fenofibrate on chronic cholestatic liver injury. Ppara-null (KO) mice were used to explore PPARα's role in the therapeutic outcome.
Fenofibrate, administered at 25 mg/kg twice daily, substantially reversed ANIT-induced chronic cholestatic liver injury shown by biochemical and pathological end points. The modifications of bile acid metabolism were found to be adaptive responses. The JNK-AP1-CCL2/CXCL2 axis was activated in all the mice administered ANIT which developed chronic cholestatic liver injury. But it was substantially decreased by fenofibrate in WT mice rather than that in KO mice.
Low-dose fenofibrate reversed chronic cholestatic liver injury in mice. The therapeutic action was dependent on PPARα activation and occurred by inhibiting chemotaxis via the JNK-AP1-CCL2/CXCL2 signaling. These data provided an exciting basis for optimization of therapeutic fenofibrate regimen in the clinic. Additionally, they suggested anti-chemotaxis of low-dose fenofibrate in single therapy to treat cholestatic liver diseases.
已有报道称，非诺贝特与熊去氧胆酸联合使用对胆汁淤积症有益。然而，其作为单一疗法治疗慢性胆汁淤积症的治疗作用及其潜在机制尚不清楚。
本研究中，采用 0.05% ANIT 饮食对野生型（WT）小鼠进行处理，以模拟慢性胆汁淤积性肝损伤。采用 25mg/kg 非诺贝特对小鼠进行 2 次/d 给药，共 10d，以研究非诺贝特对慢性胆汁淤积性肝损伤的治疗作用。采用 Ppara 基因敲除（KO）小鼠探索 PPARα 在治疗结果中的作用。
25mg/kg 非诺贝特 2 次/d 给药可显著逆转 ANIT 诱导的慢性胆汁淤积性肝损伤，表现为生化和病理终点的改善。胆汁酸代谢的改变被认为是适应性反应。在所有接受 ANIT 处理并发生慢性胆汁淤积性肝损伤的小鼠中，JNK-AP1-CCL2/CXCL2 轴被激活，但在 WT 小鼠而非 KO 小鼠中，该轴被非诺贝特显著抑制。
低剂量非诺贝特可逆转小鼠的慢性胆汁淤积性肝损伤。该治疗作用依赖于 PPARα 的激活，通过抑制 JNK-AP1-CCL2/CXCL2 信号转导来实现趋化作用。这些数据为优化临床治疗用非诺贝特方案提供了令人兴奋的基础。此外，这些数据还提示低剂量非诺贝特在单一疗法中具有抗趋化作用，可用于治疗胆汁淤积性肝病。
