12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain
12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain
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花生四烯酸的 12/15-脂氧合酶代谢物激活 PPARγ：缺血脑中可能的神经保护作用
DOI：
10.1194/jlr.m053058
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发表时间：
2015-03-01
影响因子：
6.5
通讯作者：
Cheng, Yan
中科院分区：
文献类型：
--
作者：
Sun, Li;Xu, Yan-Wei;Cheng, Yan
12/15-脂氧合酶（LOX）氧化各种游离脂肪酸，包括花生四烯酸（AA）。在大脑中，AA的主要12/15- lox代谢物是12(S)-HETE和15(S)-HETE。PPARγ是一种核受体，其激活通过其抗炎特性具有神经保护作用。在这项研究中，我们研究了12(S)-和15(S)- hete参与脑缺血后PPARγ的调节及其对缺血诱导炎症反应的影响。我们在这里显示了12/15- lox的表达增加，主要在神经元中，并且在缺血脑中12(S)-HETE和15(S)-HETE的产生升高。外源性12(S)-和15(S)- hete增加缺血大鼠PPARγ蛋白水平、核易位和dna结合活性，提示PPARγ活化。当12(S)-或15(S)- hete孵育时，初级皮质神经元中PPARγ转录活性增加，进一步证实了这一效应。此外，12(S)-和15(S)- hete均能有效抑制缺血大鼠核因子-κ b、诱导型NO合酶和环氧合酶-2的诱导，并引起神经保护作用。PPARγ拮抗剂GW9662逆转12(S)-和15(S)- hete对促炎因子的作用表明它们的作用是通过PPARγ介导的。因此，脑缺血时12(S)-和15(S)- hete的诱导提示可能产生内源性神经保护信号。
The enzyme 12/15-lipoxygenase (LOX) oxidizes various free fatty acids, including arachidonic acid (AA). In the brain, the principal 12/15-LOX metabolites of AA are 12(S)-HETE and 15(S)-HETE. PPARγ is a nuclear receptor whose activation is neuroprotective through its anti-inflammatory properties. In this study, we investigate the involvement of 12(S)- and 15(S)-HETE in the regulation of PPARγ following cerebral ischemia and their effects on ischemia-induced inflammatory response. We show here the increased expression of 12/15-LOX, predominantly in neurons, and elevated production of 12(S)-HETE and 15(S)-HETE in ischemic brain. The exogenous 12(S)- and 15(S)-HETE increase PPARγ protein level, nuclear translocation, and DNA-binding activity in ischemic rats, suggesting the activation of PPARγ. This effect was further confirmed by showing the increased PPARγ transcriptional activity in primary cortical neurons when incubated with 12(S)- or 15(S)-HETE. Moreover, both 12(S)- and 15(S)-HETE potently inhibited the induction of nuclear factor-κB, inducible NO synthase, and cyclooxygenase-2 in ischemic rats, and elicited neuroprotection. The reversal of the effects of 12(S)- and 15(S)-HETE on pro-inflammatory factors by PPARγ antagonist GW9662 indicated their actions were mediated via PPARγ. Thus, the induction of 12(S)- and 15(S)-HETE during brain ischemia suggests that endogenous signals of neuroprotection may be generated.