Hepatic stimulator substance inhibits calcium overflow through the mitochondria-associated membrane compartment during nonalcoholic steatohepatitis
Hepatic stimulator substance inhibits calcium overflow through the mitochondria-associated membrane compartment during nonalcoholic steatohepatitis
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非酒精性脂肪性肝炎期间，肝刺激物质抑制钙通过线粒体相关膜室溢出
DOI：
10.1038/labinvest.2016.139
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发表时间：
2017-03-01
影响因子：
5
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Xiao, Fan;Zhang, Jing;An, Wei
非酒精性脂肪肝被认为是内质网 (ER) 和线粒体的疾病。最近的研究表明，内质网和线粒体膜有 15-20% 的重叠，该区域被称为“线粒体相关内质网膜”(MAM)。一些蛋白质，包括 sarco/ER 钙 ATP 酶 (SERCA)，位于 MAM 中，在 ER 和线粒体之间的 Ca2+ 信号传导和稳态中发挥重要作用。我们之前的研究表明，肝刺激物质（HSS）可以抑制活性氧诱导的内质网应激，从而减少线粒体！损害。然而，HSS 对 ER 和 ER-线粒体相互作用的保护作用的机制仍不清楚。在这项研究中，我们证实HSS的外源表达可以保护非酒精性脂肪性肝炎小鼠的肝脏免受脂肪变性。更重要的是，HSS提供的保护使MAM室中的SERCA能够良好地发挥作用，防止胞质游离Ca2+大量流入线粒体，从而保护线粒体功能免受钙超载，并缓解棕榈酸诱导的肝细胞脂肪变性。我们的结果表明，HSS 对 SERCA 表达的保护作用与 MAM 内钙稳态的维持有关，从而改善 ER 和线粒体之间紊乱的 Ca2+ 通讯。
Nonalcoholic fatty liver disease is considered a disorder of the endoplasmic reticulum (ER) and mitochondria. Recent studies have shown that the ER and mitochondrial membranes overlap by 15-20%, a region referred to as the 'mitochondria-associated ER membrane' (MAM). Some proteins, including sarco/ER calcium ATPase (SERCA), are located in the MAM and have an important role in Ca2+ signaling and homeostasis between the ER and the mitochondria. Our previous study showed that hepatic stimulator substance (HSS) inhibits the ER stress induced by reactive oxygen species, thus reducing mitochondria! damage. However, the mechanism underlying the protective effect of HSS on the ER and ER-mitochondrial interaction remains unclear. In this study, we confirmed that the exogenous expression of HSS protected the liver from steatosis in mice with nonalcoholic steatohepatitis. More importantly, the protection provided by HSS allowed SERCA in the MAM compartment to function well, preventing the extensive influx of cytosolic free Ca2+ to the mitochondria, thus preserving the mitochondrial functions from calcium overload and relieving palmitic-acid-induced hepatocyte steatosis. Our results suggest that the protective effect of HSS on SERCA expression is associated with the maintenance of calcium homeostasis within the MAM, thus ameliorating the disordered Ca2+ communication between the ER and mitochondria.