tert-Butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation.
tert-Butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation.
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叔丁基氢醌 (tBHQ) 通过诱导自噬来保护肝细胞免受脂毒性，而与 Nrf2 激活无关。
DOI：
10.1016/j.bbalip.2013.09.004
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Song Z
中科院分区：
文献类型：
--
作者：
Li S;Li J;Shen C;Zhang X;Sun S;Cho M;Sun C;Song Z
饱和脂肪酸（sfa）诱导肝细胞死亡，其中氧化应激机制参与。核因子（红细胞衍生2）样2 （Nrf2）是细胞抗氧化防御酶的主要转录调控因子。因此，Nrf2激活被认为是对抗氧化应激引发的细胞损伤的有效策略。在本研究中，我们首先利用广泛使用的Nrf2激活剂叔丁基对苯二酚（tBHQ）来研究Nrf2激活在sfas诱导的肝毒性中的潜在保护作用。正如预期的那样，在AML-12小鼠肝细胞和HepG2人肝癌细胞中，thbhq都能阻止sfas诱导的肝细胞死亡。然而，tBHQ的保护作用与Nrf2无关，因为sirna介导的Nrf2沉默并没有取消tBHQ赋予的保护作用。另外，我们的研究结果表明，自噬激活在thbhq对脂肪毒性的保护作用中起着关键作用。thbhq诱导自噬激活，自噬抑制剂可消除thbhq的保护作用。通过增加LC3斑点的积累、LC3- ii转化和自噬通量（在蛋白水解抑制剂存在下LC3- ii转化），thbhq暴露诱导了自噬。随后的机制研究发现，暴露于tBHQ可激活amp活化蛋白激酶（AMPK）， sirna介导的AMPK基因沉默可消除tBHQ诱导的自噬激活，表明AMPK在tBHQ触发的自噬诱导中起关键作用。此外，我们的研究提供了证据，证明thbhq诱导的自噬激活是其nrf2激活特性所必需的。总的来说，我们的数据揭示了thbhq保护肝细胞免受sfas诱导的脂肪毒性的新机制。thbhq触发的自噬诱导不仅具有肝保护作用，还具有nrf2激活特性。
Saturated fatty acids (SFAs) induce hepatocyte cell death, wherein oxidative stress is mechanistically involved. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcriptional regulator of cellular antioxidant defense enzymes. Therefore, Nrf2 activation is regarded as an effective strategy against oxidative stress-triggered cellular damage. In this study, tert-butylhydroquinone (tBHQ), a widely used Nrf2 activator, was initially employed to investigate the potential protective role of Nrf2 activation in SFAs-induced hepatoxicity. As expected, SFAs-induced hepatocyte cell death was prevented by tBHQ in both AML-12 mouse hepatocytes and HepG2 human hepatoma cells. However, the protective effect of tBHQ is Nrf2-independent, because the siRNA-mediated Nrf2 silencing did not abrogate tBHQ-conferred protection. Alternatively, our results revealed that autophagy activation was critically involved in the protective effect of tBHQ on lipotoxicity. tBHQ induced autophagy activation and autophagy inhibitors abolished tBHQ’s protection. The induction of autophagy by tBHQ exposure was demonstrated by the increased accumulation of LC3 puncta, LC3-II conversion, and autophagic flux (LC3-II conversion in the presence of proteolysis inhibitors). Subsequent mechanistic investigation discovered that tBHQ exposure activated AMP-activated protein kinase (AMPK) and siRNA-mediated AMPK gene silencing abolished tBHQ-induced autophagy activation, indicating that AMPK is critically involved in tBHQ-triggered autophagy induction. Furthermore, our study provided evidence that tBHQ-induced autophagy activation is required for its Nrf2-activating property. Collectively, our data uncover a novel mechanism for tBHQ in protecting hepatocytes against SFAs-induced lipotoxicity. tBHQ-triggered autophagy induction contributes not only to its hepatoprotective effect, but also to its Nrf2-activating property.
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影响因子：
4.6
作者：
Jin W;Ni H;Dai Y;Wang H;Lu T;Wu J;Jiang J;Liang W
通讯作者：
Liang W
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
25.7
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
通讯作者：
Gores GJ
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M