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）和睡眠片段化（SF）。SA是一种常见疾病，在美国有4%的男性和2%的女性，这在影响超过50%的肥胖个体的肥胖症中尤其普遍。SA是心血管疾病的独立危险因素，与心肌梗死、卒中和死亡的发生率增加相关。在SA中观察到的代谢紊乱，特别是胰岛素抵抗和血脂异常，有助于心血管发病率。SA与独立于肥胖的高胆固醇血症相关。EH和SF都可能影响代谢功能，目前建议的主要目的是确定SA导致脂质代谢失调的途径和机制。我们建议，IH，而不是SF无缺氧，导致高脂血症和上调肝脏中的脂质代谢。我们预期高血压将增加血浆脂质水平在瘦和肥胖的人。我们推测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中的脂质生物合成。最后，我们预测IH会减弱降脂治疗的疗效。我们的方法是检查验证模型的IH和SF在瘦和肥胖的近交系小鼠的影响，探索SREBP通路使用特定的转基因小鼠的功能意义，并检查EH和降脂治疗之间的相互作用。我们将采用最先进的技术，真实的时间PCR，定量蛋白质和脂质生物化学，脂质生物合成和脂蛋白清除体内。具体而言，我们建议：（1）检测不同严重程度IH和非缺氧SF期间瘦小鼠的血脂水平、肝脏中的脂质水平和脂质生物合成，以及肝脏中脂质生物合成酶的表达;（2）检测饮食性肥胖和遗传性肥胖存在时IH对血脂和脂质生物合成的影响（db/db和金黄色葡萄球菌小鼠）;（3）确定SREBP通路的敲除是否改变对EH的代谢反应;（4）探索EH和具有体重减轻和HMG-CoA还原酶抑制剂的降脂治疗之间的相互作用。该提案将阐明SA与脂质代谢失调之间的因果关系，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.