Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
Lipids Health Dis. 2013 Feb 6;12:11. doi: 10.1186/1476-511X-12-11.
Peroxisome proliferator activated receptor alpha (PPARα) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARα in ethanol induced liver fibrosis in mice.
C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARα agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARα induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed.
The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARα and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury.
The present study provides evidence for the protective role of PPARα induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors.
过氧化物酶体增殖物激活受体α（PPARα）可改善乙醇诱导的肝脂肪变性。然而，其在酒精性肝纤维化中的作用尚未完全阐明。本研究旨在阐明 PPARα在乙醇诱导的小鼠肝纤维化中的作用及其分子机制。
C57BL/6J 小鼠给予含 4%乙醇的 Lieber-DeCarli 液体饮食 8 周，最后 4 周腹腔注射 5%四氯化碳（CCl4）诱导酒精性肝纤维化。在最后几周给小鼠注射 PPARα激动剂 WY14643。评估 PPARα诱导对肝组织学、肝星状细胞（HSCs）活化以及肝内炎症和纤维化因子表达的影响。
乙醇加 CCl4 处理的小鼠表现出进行性肝损伤，包括肝细胞碎片状坏死、严重的炎症细胞浸润和桥接纤维化。这伴随着肝内 PPARα和保护性细胞因子脂联素、血红素加氧酶-1 和白细胞介素-10 的表达下调。此外，促炎细胞因子肿瘤坏死因子-α以及促纤维化基因骨桥蛋白、转化生长因子-β1、内脏脂肪素、磷脂酰肌醇 3-激酶、基质金属蛋白酶-2（MMP-2）和 MMP-9 的表达上调。WY14643 治疗恢复了乙醇加 CCl4 处理改变的细胞因子表达，并同时改善了肝损伤。
本研究为 PPARα诱导通过调节炎症和纤维化因子改善乙醇介导的纤维化提供了证据。
