Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure.
Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure.
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DOI：
10.1242/dmm.023242
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发表时间：
2016-07-01
影响因子：
4.3
通讯作者：
Duan Z
中科院分区：
文献类型：
--
作者：
Zhang L;Ren F;Zhang X;Wang X;Shi H;Zhou L;Zheng S;Chen Y;Chen D;Li L;Zhao C;Duan Z
过氧化物酶体增殖物激活受体α（Peroxisome proliferator-activated receptor α，PPARα）是缓解急性肝衰竭（acute liver failure，ALF）时肝损伤的关键调节因子。然而，其监管机制在很大程度上仍未确定。内质网应激（Endoplasmic reticulum stress，ER stress）在许多肝脏疾病中起重要作用。本研究旨在探讨激活PPARα是否能抑制内质网应激诱导的肝细胞凋亡，从而保护肝细胞免受ALF的侵害。在D-半乳糖胺（D-GalN）和脂多糖（LPS）诱导的ALF小鼠模型中，给予Wy-14643以激活PPARα，给予4-苯基丁酸（4-PBA）以减弱ER应激。与对照组相比，PPARα激活可改善肝损伤，因为预先给予其特异性诱导剂Wy-14643可降低血清转氨酶水平并保护肝脏结构。PPARα激活的保护作用是通过抑制内质网应激诱导的肝细胞凋亡实现的。（1）激活PPARα可降低葡萄糖调节蛋白78（Grp 78）、Grp 94和C/EBP同源蛋白（CHOP）的表达;（2）4-PBA预处理促进了肝脏组织中PPARα的表达，小干扰RNA（siRNA）抑制PPARα可逆转肝保护作用，增加肝细胞凋亡;（3）Wy-14643体外激活PPARα可减少重度内质网应激诱导的肝细胞凋亡，siRNA抑制PPARα可减少轻度内质网应激诱导的肝细胞存活。在这里，我们证明了在ALF中，特别是通过调节ER应激，PPARα激活有助于肝脏保护和减少肝细胞凋亡。因此，靶向治疗PPARα可能是改善ALF的潜在治疗策略。总结：在D-GalN/LPS诱导的急性肝衰竭小鼠模型中，上调PPARα可通过抑制ER应激介导的肝细胞凋亡来减轻肝损伤。
Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF. Summary: Upregulation of PPARα can ameliorate hepatic injury by inhibiting ER stress-mediated hepatocyte apoptosis in a mouse model of D-GalN/LPS-induced acute liver failure.