Department of Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang, P. R. China.
Department of Health Management, Ningbo College of Health Sciences, Ningbo, Zhejiang, P. R. China.
Pharmazie. 2021 Feb 25;76(2):103-108. doi: 10.1691/ph.2021.0988.
Cholestatic liver fibrosis occurs in liver injuries accompanied by inflammation, which develops into cirrhosis if not effectively treated in early stage. The aim of the study is to explore the effect of fenofibrate on liver fibrosis in chronic cholestatic mice. In this study, wild-type (WT) and Pparα-null (KO) mice were dosed alpha-naphthylisothiocyanate (ANIT) diet to induce chronic cholestasis. Induced liver fibrosis was determined by pathological biomarkers. Then fenofibrate 25 mg/kg was orally administrated to mice twice/day for 14 days. Serum and liver samples were collected for analysis of biochemistry and fibrosis. In WT mice, cholestatic biomarkers were increased by 5-8-fold and the expression of tissue inhibitors of metalloproteinases 1 (TIMP-1), Monocyte chemoattractant protein 1 (MCP-1), Collagen protein I (Collagen I) was increased by more than 10-fold. Fenofibrate significantly downgraded the biochemical and fibrotic biomarkers. In Western blot analysis, levels of collagenI and alpha-smooth muscle actin (α-SMA) were strongly inhibited by fenofibrate. In KO mice, liver fibrosis was induced successfully, but no improvement after fenofibrate treatment was observed. These data showed low-dose fenofibrate reverses cholestatic liver fibrosis in WT mice but not in KO mice, suggesting the dependence of therapeutic action on peroxisome proliferator-activated receptor alpha (PPARα). The study offers an additional therapeutic strategy for cholestatic liver fibrosis in practice.
胆汁淤积性肝纤维化发生在伴有炎症的肝损伤中，如果在早期得不到有效治疗，就会发展为肝硬化。本研究旨在探讨非诺贝特对慢性胆汁淤积性小鼠肝纤维化的影响。在这项研究中，野生型（WT）和过氧化物酶体增殖物激活受体α 基因敲除（KO）小鼠给予α-萘异硫氰酸酯（ANIT）饮食诱导慢性胆汁淤积。通过病理生物标志物来确定诱导的肝纤维化。然后，非诺贝特 25mg/kg 每天两次口服给药 14 天。收集血清和肝组织样本进行生化和纤维化分析。在 WT 小鼠中，胆汁淤积生物标志物增加了 5-8 倍，组织金属蛋白酶抑制剂 1（TIMP-1）、单核细胞趋化蛋白 1（MCP-1）和胶原 I（Collagen I）的表达增加了 10 多倍。非诺贝特显著降低了生化和纤维化生物标志物。在 Western blot 分析中，胶原 I 和α-平滑肌肌动蛋白（α-SMA）的水平被非诺贝特强烈抑制。在 KO 小鼠中，成功诱导了肝纤维化，但非诺贝特治疗后没有观察到改善。这些数据表明，低剂量的非诺贝特可逆转 WT 小鼠的胆汁淤积性肝纤维化，但不能逆转 KO 小鼠的肝纤维化，表明治疗作用依赖于过氧化物酶体增殖物激活受体α（PPARα）。该研究为临床实践中胆汁淤积性肝纤维化提供了一种额外的治疗策略。
