Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice
Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice
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DOI：
10.1002/hep.21963
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发表时间：
2008-01-01
期刊：
影响因子：
13.5
通讯作者：
Lentsch, Alex B.
中科院分区：
文献类型：
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作者：
Kuboki, Satoshi;Shin, Thomas;Lentsch, Alex B.
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）在肝脏炎症和损伤中的作用尚不清楚。在这项研究中，我们试图确定的作用，过氧化物酶体增殖物激活受体γ在肝脏缺血/再灌注损伤小鼠。对雄性小鼠进行90分钟的部分肝缺血，然后进行长达8小时的再灌注。发现在肝细胞中组成型激活，但在非实质细胞中不激活。诱导缺血后，肝脏PPAR γ活化迅速下降，并在整个8小时再灌注期间保持抑制。这种降低的激活不是蛋白质可用性降低的结果，因为肝核PPAR γ、类维生素A X受体-a（RXR α）和PPAR γ/RXR α异二聚体表达得以维持。伴随着过氧化物酶体增殖物激活受体γ激活的减少，天然配体15-脱氧-δ（12，14）-野牡丹素J的表达减少（2）。这与PPAR γ和共激活因子p300的相互作用减少有关。为了确定在肝缺血/再灌注损伤期间，PPAR γ激活是否具有保肝作用，用PPAR γ激动剂罗格列酮和连接肽处理小鼠。与未治疗的小鼠相比，这些治疗增加了PPAR γ活化并减少了肝损伤。此外，PPAR γ缺陷小鼠在缺血/再灌注后比野生型小鼠有更多的肝损伤。结论：这些数据表明，过氧化物酶体增殖物激活受体γ是一个重要的内源性调节剂，和潜在的治疗靶点，缺血性肝损伤。
The function of peroxisome proliferator-activated receptor-gamma (PPAR gamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPAR gamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPAR gamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPAR gamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPAR gamma, retinoid X receptor-a (RXR alpha), and PPAR gamma/RXR alpha heterodimer expression was maintained. Accompanying the decrease in PPAR gamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandinJ(2). This was associated with reduced interaction of PPAR gamma and the coactivator, p300. To determine whether PPAR gamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPAR gamma agonists, rosiglitazone and connecting peptide. These treatments increased PPAR gamma activation and reduced liver injury compared to untreated mice. Furthermore, PPAR gamma-deficient mice had more liver injury after ischemia/reperfusion than their wildtype counterparts. Conclusion: These data suggest that PPAR gamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.