肝脏SERCA/UPR通路在慢性间歇低氧致胰岛素抵抗中的作用研究

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is an independent risk factor of type 2 diabetes mellitus(T2DM). Insulin resistance (IR) caused by chronic intermittent hypoxia (CIH) is essential in linking OSAHS with its systemic damages. In our preliminary study, we found that CIH exposure caused IR in mice, and the phosphorylation of Akt in the insulin signaling pathway was reduced. Changes in insulin signaling pathway was associated with the activation of ERS/UPR pathway. However, the upstream mechanisms underlying ERS induced by CIH and the critical cites of action were not fully understood. Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is an important modifying factor of ERS. In our preliminary study, we also found that SERCA2b protein and mRNA levels were dramatically reduced in mice liver and HepG2 cell after CIH exposure. Based on the research background and our discovery in the preliminary study, we hypothesize here that OSAHS and its characteristic CIH could cause changes in SERCA/UPR pathway in liver, interfere with insulin signaling and consequently cause IR. In order to verify this hypothesis, we will initially detect roles of hepatic SERCA/UPR pathway in the regulation of insulin signaling pathway. And secondly the proteomic landscape of hepatic ER will be examined to explore the critical downstream proteins of SERCA under CIH exposure. Detection of changes and critical sites of action in these pathways may help further elucidate molecular mechanisms underlying CIH-induced IR and lay foundation for the further exploration of potential therapeutic targets for systemic damages caused by OSAHS.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是2型糖尿病的独立危险因素，其关键机制是慢性间歇低氧（CIH）所致胰岛素抵抗（IR）。我们研究发现CIH可致小鼠IR,并影响肝细胞胰岛素受体后信号转导，且与内质网应激（ERS）/未折叠蛋白反应（UPR）及下游炎症通路活化相关。然而，CIH致ERS的分子机制和关键信号转导蛋白未明。肌浆网/内质网钙ATP酶（SERCA）是ERS的重要调控因子。我们还发现，CIH可致小鼠肝脏和肝细胞SERCA活化水平降低。因此推测，CIH可能通过SERCA启动ERS(即SERCA/UPR通路)介导IR。本研究拟从动物和细胞水平，研究CIH下肝脏SERCA/UPR通路的变化及其对胰岛素信号转导的影响，探讨上述通路在CIH致IR中的作用；应用蛋白质组学技术筛选SERCA调控ERS的下游关键分子，探寻治疗靶点。为阐释OSAHS致IR的分子机制及代谢损害的综合防治提供依据。

阻塞性睡眠呼吸暂停低通气综合征（OSA）是2型糖尿病的独立危险因素，其关键机制是慢性间歇低氧（CIH）所致胰岛素抵抗（IR）。我们分别在动物水平和细胞水平证实了SERCA在CIH引起肝脏内质网应激（ERS），进而导致胰岛素抵抗和糖代谢异常中的重要作用。并通过蛋白质组学技术筛选发现ERS相关通路PERK/eIF-2a可有望成为潜在的治疗靶点。同时，研究发现探索ERS及其伴随的细胞自噬具有交互作用，可对进一步明确CIH下IR发生的分子机制，阐明OSA所致代谢紊乱疾病提供理论依据，进而为OSA所致的代谢紊乱的综合防治提供新思路。