慢性间歇低氧对肝细胞线粒体自噬的影响及脂联素干预效应和机理的研究

Obstructive sleep apnea syndrome (OSAS) can lead to damage of multiple target organs including liver such as non-alcoholic fatty liver disease (NAFLD). Further studies are needed to find exact mechanisms of OSAS associated hepatic injuries as well as associated prevention and treatment. Our previous studies revealed that chronic intermittent hypoxia (CIH), a pathological condition mimic to OSAS, could cause liver to suffer oxidative stress and endoplasmic reticular stress, mitochondrial injury, enhanced hepatocyte apoptosis，impaired hepatic function and increased lipid deposition.Our recent prelimilary test suggested CIH induced cell apoptosis was very possibly associated CIH induced reduction in hepatocyte motochondrial autophagy. In addition, adiponectin (Ad) might have the potential capability to enhance the autophacy. The effects of CIH on hepatocyte motochondrial have not been reported. Ad, as a adopocytin, was reported to be able to enhance autophagy in myocytes and therefore to increase contractility of myocardium. In view of these, we speculate that the mechanisms of CIH induced hepatic injury was highly possibly associated with weakened hepatocyte mitochondrial autophagy. In this study, we expect to investigate the the effects of CIH on hepatocyte mitochondrial autophagy and intervention role and associated mechanisms of Ad..Therefore, this study can provide theoretic basis for elucidating mechanisms of OSAS induced hepatic injury and explore the thinking for novel prevention and treatment.

阻塞性睡眠呼吸暂停综合征（OSAS）可致多种靶器官损伤，包括肝损伤如非酒精性脂肪性肝病（NAFLD）。对OSAS相关肝损伤的确切机制及防治有待深入研究。我们的前期研究发现模拟OSAS病理的慢性间歇低氧（CIH）可引起肝氧化和内质网应激反应，线粒体损伤、细胞凋亡增加、肝功损害和脂质含量增高。近期的预实验又发现CIH所致的细胞凋亡增加很可能与CIH导致对肝细胞线粒体的自噬能力降低有关，且脂联素（Ad）也提示具备提高肝细胞线粒体自噬能力的潜在作用。CIH是否影响肝细胞线粒体自噬尚无报道。Ad作为脂肪因子，曾被报道可提高心肌细胞线粒体自噬能力和心肌收缩功能。我们推测CIH诱发肝损伤的重要机制极可能与肝细胞线粒体自噬改变相关。本课题拟通过系列实验探讨CIH对肝细胞线粒体自噬的影响 以及Ad的干预效应及i机制，为进一步阐明OSAS肝损伤及功能障碍的机制提供理论基础，也为寻找新的防治方法提供理论基础。

本项目针对阻塞性睡眠呼吸暂停综合征（OSAS）可致的肝损伤如非酒精性脂肪性肝病（NAFLD）的发生机制及可能的防治开展了动物和临床病例的实验和探讨。初期的研究发现模拟OSAS病理的慢性间歇低氧（CIH）可引起肝氧化和内质网应激反应，线粒体损伤、细胞凋亡增加和肝功损害。进一步实验又发现CIH所致的细胞凋亡增加与CIH导致对肝细胞线粒体的自噬能力降低有关，且脂联素（Ad）也提示具备提高肝细胞线粒体自噬能力的潜在作用。因此认为CIH诱发肝损伤的重要机制与肝细胞线粒体自噬水平下调相关。临床病例部分的探讨探究了中重度OSAS与NAFLD关系，发现在347例中重度OSA患者中，患脂肪肝组夜间低氧程度重于非脂肪肝组，而脂肪肝指数（FLI）是预测患者有无脂肪肝的良好指标。本课题通过系列实验探讨CIH对肝细胞线粒体自噬的影响 以及Ad的干预效应及i机制，为进一步阐明OSAS肝损伤及功能障碍的机制提供了理论基础和Ad有效治疗治疗思路。