Sleep Apnea and Dysregulation of Lipid Metabolism

描述（由申请人提供）：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，导致间歇性缺氧（IH）和睡眠碎片化（SF）。SA是一种常见病，在美国有4%的男性和2%的女性患有SA，在肥胖人群中尤为普遍，影响超过50%的肥胖者。SA是心血管疾病的独立危险因素，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，有助于心血管疾病的发病率。SA与高胆固醇血症相关，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确定SA导致脂质代谢失调的途径和机制。我们认为IH会导致高脂血症和肝脏脂质代谢上调，而不缺氧的SF则不会。我们预计EH会增加瘦和肥胖个体的血脂水平。我们假设EH通过固醇调节元件结合蛋白1 （SREBP 1）控制的途径上调肝脏脂质生物合成。最后;我们预测IH会减弱降脂治疗的效果。我们的方法是在瘦型和肥胖型近交系小鼠中检验经验证的IH和SF模型的作用，利用特定转基因小鼠探索SREBP通路的功能意义，并检验EH与降脂治疗之间的相互作用。我们将采用最先进的实时PCR技术，定量蛋白质和脂质生物化学，脂质生物合成和体内脂蛋白清除。具体而言，我们建议：(1)检测不同严重程度IH和非缺氧性SF期间瘦小鼠血浆脂质水平、肝脏脂质水平和生物合成以及肝脏脂质生物合成酶的表达；(2)研究在饮食性肥胖和遗传性肥胖的情况下，IH对血浆脂质和脂质生物合成的影响（db/db和豚鼠黄鼠）；(3)确定敲除SREBP通路是否会改变对EH的代谢反应；(4)探讨EH与降脂治疗与减肥和HMG-CoA还原酶抑制剂之间的相互作用。该建议将阐明SA与脂质代谢失调的致病途径，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.