Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
Menchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China.
Inflamm Res. 2017 Sep;66(9):813-822. doi: 10.1007/s00011-017-1061-3. Epub 2017 Jun 9.
Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to ameliorate liver injury in cases of acute liver failure (ALF). However, its intrinsic protective molecular mechanisms remain largely undetermined. C/EBP homologous protein (CHOP) is an important mediator of lipopolysaccharide (LPS)-induced inflammation. The aim of the present study was to test the hypothesis that PPARα activation alleviates liver inflammation to protect mice from acute liver failure (ALF) mediated by CHOP.
In a murine model induced by D-galactosamine (D-GalN, 700 mg/kg) and LPS (10 μg/kg), Wy-14643 (6 mg/kg) was administered to activate PPARα. The mice of different groups were killed 6 h after D-GalN/LPS injection, and the liver and blood were collected for analysis. To find out whether PPARα activation protects the liver from injury due to inflammation by regulating CHOP, we used expression plasmid to increase CHOP expression and demonstrated how PPARα mediated CHOP to regulate inflammation in vivo and in vitro.
The expression of PPARα was downregulated and the expression of CHOP was upregulated with the development of D-GalN/LPS-induced liver injury. The protective molecular mechanisms of PPARα activation were dependent on the expression of CHOP. Indeed, (1) PPARα activation decreased the expression of CHOP; on the other hand, PPARα knockdown increased the expression of CHOP in vivo; (2) the depressed liver inflammation by PPARα activation was due to the downregulation of CHOP expression, because overexpression of CHOP by transfect plasmid reversed liver protection and increased liver inflammation again; (3) in vitro, PPARα inhibition by siRNA treatment increased the expression of proinflammatory cytokines, and CHOP siRNA co-transfection reversed the expression of proinflammatory cytokines.
Here, we demonstrated that PPARα activation contributes to liver protection and decreases liver inflammation in ALF, particularly through regulating CHOP. Our findings may provide a rationale for targeting PPARα as a potential therapeutic strategy to ameliorate ALF.
过氧化物酶体增殖物激活受体 α（PPARα）的激活已被报道可改善急性肝衰竭（ALF）中的肝损伤。然而，其内在的保护分子机制在很大程度上仍未确定。C/EBP 同源蛋白（CHOP）是脂多糖（LPS）诱导炎症的重要介质。本研究旨在测试以下假设：PPARα 的激活可减轻肝脏炎症，从而保护小鼠免受 CHOP 介导的急性肝衰竭（ALF）。
在 D-半乳糖胺（D-GalN，700mg/kg）和 LPS（10μg/kg）诱导的小鼠模型中，给予 Wy-14643（6mg/kg）激活 PPARα。不同组的小鼠在 D-GalN/LPS 注射后 6 小时处死，并采集肝脏和血液进行分析。为了确定 PPARα 的激活是否通过调节 CHOP 来保护肝脏免受炎症引起的损伤，我们使用表达质粒增加 CHOP 的表达，并在体内和体外证明了 PPARα 如何通过调节 CHOP 来调节炎症。
随着 D-GalN/LPS 诱导的肝损伤的发展，PPARα 的表达下调，CHOP 的表达上调。PPARα 激活的保护分子机制依赖于 CHOP 的表达。事实上，（1）PPARα 激活可降低 CHOP 的表达；另一方面，体内 PPARα 敲低增加了 CHOP 的表达；（2）PPARα 激活抑制肝炎症是由于 CHOP 表达下调所致，因为通过转染质粒过表达 CHOP 再次逆转肝保护并增加肝炎症；（3）体外，siRNA 处理抑制 PPARα 增加促炎细胞因子的表达，共转染 CHOP siRNA 逆转促炎细胞因子的表达。
在这里，我们证明了 PPARα 的激活有助于 ALF 中的肝脏保护并减少肝脏炎症，特别是通过调节 CHOP。我们的发现可能为靶向 PPARα 作为改善 ALF 的潜在治疗策略提供依据。
