Alleviation of palmitic acid-induced endoplasmic reticulum stress by augmenter of liver regeneration through IP3R-controlled Ca2+ release
Alleviation of palmitic acid-induced endoplasmic reticulum stress by augmenter of liver regeneration through IP3R-controlled Ca2+ release
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通过 IP3R 控制的 Ca2 释放促进肝脏再生，减轻棕榈酸诱导的内质网应激
DOI：
10.1002/jcp.26463
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发表时间：
2018-08-01
影响因子：
5.6
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Xiao, Wei-chun;Zhang, Jing;An, Wei
内质网Ca ~（2+）的异常释放导致内质网应激，与非酒精性脂肪肝的发病密切相关。我们先前报道了肝再生增强因子（ALR）减轻内质网应激并保护肝细胞免受脂毒性。然而，ALR保护和ER应激抑制之间的联系仍不清楚。在这项研究中，我们研究了ALR对肝脏脂肪变性的保护作用是否与其抑制钙从ER溢出到线粒体有关。软脂酸（PA）处理HepG 2细胞可上调IP 3R表达，触发内质网内Ca 2+释放，诱导内质网应激。然而，在ALR转染（ALR-Tx）HepG 2细胞，PA诱导的细胞损伤明显减轻相比，在载体Tx细胞。PA处理后，ALR-Tx细胞IP 3R表达下调，ER应激被有效抑制，ER-Ca 2+释放和线粒体Ca 2+摄取均低于vector-Tx细胞。用shRNA敲低ALR表达消除了ALR转染所提供的保护作用。PA处理还抑制了HepG 2细胞中BCL-2和IP 3R之间的相互作用，而这种相互作用在ALR-Tx细胞中大大增强，有效地减少了IP 3R介导的ER-Ca 2+释放，从而减少了线粒体Ca 2+内流。我们的研究结果表明，ER应激的抑制ALR与BCL 2和IP 3R之间的相互作用的中断，展示了一种新的机制，ER应激的ALR-Tx细胞的抵抗。
The aberrant release of Ca2+ from the endoplasmic reticulum (ER) contributes to the onset of ER stress, which is closely related to the pathogenesis of non-alcoholic fatty liver disease. We previously reported that augmenter of liver regeneration (ALR) alleviates ER stress and protects hepatocytes from lipotoxicity. However, the link between ALR protection and the suppression of ER stress remains unclear. In this study, we investigated whether the protection against liver steatosis afforded by ALR is related to its inhibition of calcium overflow from the ER to the mitochondria. The treatment of HepG2 cells with palmitic acid (PA) upregulated IP3R expression, triggering ER-luminal Ca2+ release and inducing ER stress. However, in ALR-transfected (ALR-Tx) HepG2 cells, PA-induced cell injury was clearly alleviated compared with that in vector-Tx cells. After exposure to PA, IP3R expression was downregulated and ER stress was effectively inhibited in the ALR-Tx cells, and ER-Ca2+ release and simultaneous mitochondrial Ca2+ uptake were lower than those in vector-Tx cells. The knockdown of ALR expression with shRNA abolished the protective effects afforded by ALR transfection. PA treatment also suppressed the interaction between BCL-2 and IP3R in HepG2 cells, whereas this interaction was massively enhanced in the ALR-Tx cells, effectively reducing the IP3R-mediated ER-Ca2+ release and thus mitochondrial Ca2+ influx. Our results suggest that the inhibition of ER stress by ALR is related to the interruption of the interaction between BCL2 and IP3R, demonstrating a novel mechanism of ER stress resistance in ALR-Tx cells.