Importance of peroxisome proliferator-activated receptor-γ in hepatic ischemia/reperfusion injury in mice
Importance of peroxisome proliferator-activated receptor-γ in hepatic ischemia/reperfusion injury in mice
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DOI：
10.1016/j.jhep.2007.07.030
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发表时间：
2007-12-01
影响因子：
25.7
通讯作者：
Nakajima, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Akahori, Takahiro;Sho, Masayuki;Nakajima, Yoshiyuki
背景/目的：PPARy是核受体超家族的一种转录因子。最近的研究表明，PPARy调节炎症反应，PPARy特异性激动剂对不同器官中的几种疾病有有益的影响。然而，PPAR-γ在急性肝损伤中的确切作用尚不清楚。方法：我们研究了PPAR-γ的病理生理作用以及选择性PPARy激动剂吡格列酮对肝脏缺血/再灌注(I/R)损伤的影响。血清学和组织学分析表明，吡格列酮治疗可显著抑制肝脏I/R损伤。其保护作用与下调再灌流后多种致炎细胞因子、趋化因子和黏附分子的局部表达有关。中性粒细胞聚集也受到抑制。此外，该药还可抑制肝细胞凋亡的诱导。结论：PPAR-γ对肝脏I/R损伤有抑制作用，选择性激动剂的刺激有明显的有益作用。因此，PPAR-γ可能成为保护肝脏免受急性损伤的新的治疗靶点。(C)2007年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims: Peroxisome proliferator-activated receptor-gamma (PPARy) is a transcriptional factor belonging to the nuclear receptor superfamily. Recent studies have suggested that PPARy regulates inflammatory responses and PPARy specific agonists have beneficial effects on several disease conditions in the various organs. However, the precise role of PPAR gamma in acute liver injury remains unknown.Methods: We investigated the pathophysiological role of PPAR gamma and the effect of the selective PPARy agonist, pioglitazone, on the hepatic ischemia/reperfusion (I/R) injury.Results: PPARy expression in the liver was upregulated after reperfusion following ischemia. Pioglitazone treatment significantly inhibited hepatic I/R injury as determined by serological and histological analyses. The protective effect was associated with downregulation of the local expression of several potent proinflammatory cytokines, chemokines and adhesion molecules after reperfusion. The neutrophil accumulation was also inhibited by the treatment. Furthermore, the treatment inhibited the induction of apoptosis on hepatocytes. Finally, pioglitazone significantly improved the mouse survival in a lethal model of hepatic I/R injury.Conclusions: PPAR gamma plays an inhibitory role in hepatic I/R injury and the stimulation by selective agonist has a significant beneficial effect. Thus, PPAR gamma may be a new therapeutic target for the protection of the liver against acute injury. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.