Sleep Apnea and Dysregulation of Lipid Metabolism

描述(申请人提供)：阻塞性睡眠呼吸暂停(SA)的特征是睡眠期间反复出现上呼吸道阻塞，导致间歇性低氧(IH)和睡眠碎片(SF)。在美国，SA是一种常见的疾病，在4%的男性和2%的女性中观察到，这种疾病在肥胖症中尤其普遍，影响到超过50%的肥胖者。SA是心血管疾病的独立危险因素，并与心肌梗死、中风和死亡的发生率增加有关。在SA中观察到的代谢紊乱，特别是胰岛素抵抗和血脂异常，导致心血管疾病的发病率。SA与高胆固醇血症有关，与肥胖无关。EH和SF都可能影响代谢功能，本研究的主要目的是明确SA导致脂代谢紊乱的途径和机制。我们认为，IH而不是SF在没有缺氧的情况下会导致高脂血症和肝脏脂质代谢的上调。我们预计高血压会增加瘦身和肥胖者的血脂水平。我们假设，EH通过类固醇调节元件结合蛋白1(SREBP 1)控制的途径上调肝脏中脂质的生物合成。最后，我们预测IH会减弱降脂治疗的疗效。我们的方法是检验在瘦小和肥胖近交系小鼠中验证的IH和SF模型的效果，使用特定的转基因小鼠来探索SREBP通路的功能意义，并检查EH和降脂治疗之间的相互作用。我们将使用最先进的实时聚合酶链式反应、定量蛋白质和脂肪生物化学、脂肪生物合成和体内脂蛋白清除技术。具体地说，我们建议：(1)检测不同严重程度的IH期间和非缺氧性SF期间瘦小鼠的血脂水平、肝脏中的脂质水平和生物合成以及肝脏中脂质生物合成酶的表达；(2)检测IH对饮食肥胖和遗传性肥胖(db/db和刺鼠黄鼠)存在下的血脂和脂质生物合成的影响；(3)确定SREBP信号通路的敲除是否改变EH的代谢反应；(4)探讨EH和降脂治疗与减肥和HMG-CoA还原酶抑制剂之间的相互作用。该提案将阐明SA和脂代谢失调之间的致病途径，并确定预防高脂血症和降低睡眠呼吸暂停患者心血管风险的潜在干预措施。

DESCRIPTION (provided by applicant): Obstructive Sleep Apnea (SA) is characterized by recurrent upper airway obstructions during sleep leading to intermittent hypoxia (IH) and sleep fragmentation (SF). SA is a common disease observed in 4% of men and 2% of women in the U.S., which is especially prevalent in obesity affecting more than 50% of obese individuals. SA is an independent risk factor for cardiovascular diseases and is associated with increased incidence of myocardial infarction, stroke, and death. Metabolic disturbances observed in SA, particularly insulin resistance and dyslipidemia, contribute to cardiovascular morbidity. SA is associated with hypercholesterolemia independent of obesity. Potentially both EH and SF may affect metabolic function, and the major purpose of the current proposal is to define the pathways and mechanisms through which SA leads to dysregulation of lipid metabolism. We propose that IH, but not SF without hypoxia, leads to hyperlipidemia and up-regulation of lipid metabolism in the liver. We anticipate that EH will increase plasma lipid levels in both lean and obese individuals. We hypothesize that EH acts by up-regulating lipid biosynthesis in the liver via pathways controlled by sterol regulatory element binding protein 1 (SREBP 1). Finally; we predict that IH will attenuate therapeutic effects of lipid lowering therapy. Our approach is to examine the effects of validated models of IH and SF in lean and obese inbred mice, to explore the functional significance of SREBP pathways using specific transgenic mice, and to examine interactions between EH and lipid lowering treatment. We will employ state-of-the-art techniques of real time PCR, quantitative protein and lipid biochemistry, lipid biosynthesis and lipoprotein clearance in vivo. Specifically, we propose: (1) to examine plasma lipid levels, lipid levels and biosynthesis in the liver, and expression of the enzymes of lipid biosynthesis in the liver of lean mice during IH of different severity and during non-hypoxic SF; (2) to examine the effects of IH on plasma lipids and lipid biosynthesis in the presence of dietary obesity and genetic obesity (db/db and agouti yellow mice); (3) to determine whether the knockout of SREBP pathways alters metabolic responses to EH; (4) to explore interactions between EH and lipid lowering therapy with weight loss and HMG-CoA reductase inhibitors. The proposal will elucidate causative pathways linking SA and dysregulation of lipid metabolism and identify potential intervention for preventing hyperlipidemia and reducing cardiovascular risk in patients with sleep apnea.