The TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes.
The TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes.
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DOI：
10.1111/jcmm.13636
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发表时间：
2018-07
影响因子：
5.3
通讯作者：
Song Z
中科院分区：
文献类型：
--
作者：
Shen C;Ma W;Ding L;Li S;Dou X;Song Z
饱和脂肪酸（SFA）诱导的脂毒性在非酒精性脂肪性肝病（NAFLD）的发展中起着病理作用;然而，确切的机制仍有待明确阐明。Toll样受体（TLR）4在激活先天免疫系统中起着重要作用。有趣的是，肝细胞表达TLR 4和TLR 4信号通路的机制。肝脏特异性TLR 4基因敲除小鼠对饮食诱导的NAFLD具有保护作用，表明肝细胞TLR 4信号通路在NAFLD发病机制中起重要作用。在此，我们使用培养的肝细胞，试图直接检查TLR 4信号通路在棕榈酸酯引起的肝毒性中的作用，并阐明潜在的机制。我们的数据表明，棕榈酸酯暴露上调肝细胞中TLR 4在mRNA和蛋白水平的表达，这与NF-κB活化有关。通过药理学和遗传学方法抑制TLR 4信号通路消除了棕榈酸诱导的细胞死亡，表明TLR 4信号通路激活有助于棕榈酸诱导的肝毒性。机制研究表明，肌醇需要酶1α（IRE 1 α）是内质网（ER）应激期间激活的三种主要信号转导途径之一，是棕榈酸酯诱导的TLR 4激活的下游靶点，并在机制上参与了TLR 4激活触发的细胞死亡。总的来说，我们的数据确定TLR 4 ‐ IRE 1 α通路激活有助于棕榈酸酯诱导的肝细胞脂毒性。我们的研究结果表明，靶向TLR 4 ‐ IRE 1 α通路可能是治疗NAFLD以及其他代谢紊乱的潜在治疗选择，脂毒性是主要的病理机制。
Lipotoxicity induced by saturated fatty acids (SFAs) plays a pathological role in the development of non‐alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be clearly elucidated. Toll‐like receptor (TLR) 4 plays a fundamental role in activating the innate immune system. Intriguingly, hepatocytes express TLR4 and machinery for TLR4 signalling pathway. That liver‐specific TLR4 knockout mice are protective against diet‐induced NAFLD suggests that hepatocyte TLR4 signalling pathway plays an important role in NAFLD pathogenesis. Herein, using cultured hepatocytes, we sought to directly examine the role of TLR4 signalling pathway in palmitate‐elicited hepatotoxicity and to elucidate underlying mechanism(s). Our data reveal that palmitate exposure up‐regulates TLR4 expression at both mRNA and protein levels in hepatocytes, which are associated with NF‐κB activation. The inhibition of TLR4 signalling pathway through both pharmacological and genetic approaches abolished palmitate‐induced cell death, suggesting that TLR4 signalling pathway activation contributes to palmitate‐induced hepatotoxicity. Mechanistic investigations demonstrate that inositol‐requiring enzyme 1α (IRE1α), one of three major signal transduction pathways activated during endoplasmic reticulum (ER) stress, is the downstream target of palmitate‐elicited TLR4 activation and mechanistically implicated in TLR4 activation‐triggered cell death in response to palmitate exposure. Collectively, our data identify that the TLR4‐IRE1α pathway activation contributes to palmitate‐elicited lipotoxicity in hepatocytes. Our findings suggest that targeting TLR4‐IRE1α pathway can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism.
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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
发表时间：
2014-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Li S;Li J;Shen C;Zhang X;Sun S;Cho M;Sun C;Song Z
通讯作者：
Song Z
影响因子：
13.5
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DOI：
10.1152/ajpgi.00301.2011
发表时间：
2012-01-01
影响因子：
4.5
作者：
Kakisaka, Keisuke;Cazanave, Sophie C.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
25.7
作者：
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通讯作者：
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影响因子：
56.9
作者：
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