Sleep Apnea and Dysregulation of Lipid Metabolism

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）导致高心血管死亡率，这归因于慢性间歇性缺氧（IH）诱导的代谢异常。我们已经开发了一种小鼠慢性IH模型，其模拟了人类OSA中的氧分布，并且已经表明IH导致血脂异常、肝脂肪变性和胰岛素抵抗。我们还表明，IH通过刺激脂质生物合成的关键肝酶硬脂酰辅酶A去饱和酶1（SCD-1）导致代谢功能障碍。我们积累的证据使我们的主要假设得以形成，即慢性IH通过两条主要途径上调SCD-1导致血脂异常和肝脂肪变性，（1）诱导肝缺氧诱导因子1（HIF-1），下游激活脂质生物合成的关键因子固醇调节元件结合蛋白1c（SREBP-1c）、肝X受体（LXR）和过氧化物酶体增殖物激活受体γ（PPAR 3），（2）交感神经系统（SNS）的激活导致肝葡萄糖输出增加和碳水化合物反应元件的上调，结合蛋白ChREBP。在具体目标#1中，我们将研究HIF-1在IH期间代谢功能障碍中的作用。我们提出IH通过HIF-1上调SCD-1，因此（A）在具有HIF-11缺陷肝脏的小鼠中，IH诱导的肝SCD-1增加、血脂异常和肝脂肪变性将被减弱;（B）在分离的肝细胞中，缺氧上调SCD-1将被HIF-11缺陷消除;（C）在小鼠肝细胞中HIF-11的组成性表达将诱导SCD-1;（D）缺氧将诱导SCD-1启动子，这种诱导将被HIF-11缺陷消除，组成型活性HIF-11将足以驱动启动子活性。在具体目标#2中，我们将确定HIF-1下游的途径，缺氧通过该途径诱导培养的肝细胞中的SCD-1。我们提出HIF-1通过增加LXR、PPAR 3和SREBP-1c的活性上调SCD-1，因此（A）缺氧或HIF-11的组成型表达引起的SCD-1上调将因LXR 1/2、PPAR 3和SREBP-1c的缺乏而减弱，并因这些转录因子的联合缺乏而消除，（B）通过缺氧或通过HIF- 11的组成型表达对SCD-1启动子的诱导将被LXR 1/2、PPAR 3和SREBP-1c的缺陷减弱，并被这些转录因子的联合缺陷消除。在具体目标#3中，我们将探索在IH期间ChREBP在肝SCD-1上调中的作用。我们认为IH通过SNS诱导ChREBP，ChREBP上调SCD-1，导致血脂异常和肝脂肪变性。我们假设（A）IH对肝ChREBP的诱导将被消除，并且通过SNS的阻断将减弱SCD-1的上调;（B）ChREBP缺乏将减弱慢性IH诱导的肝SCD- 1、血脂异常和肝脂肪变性的增加。 公共卫生相关性：阻塞性睡眠呼吸暂停会增加心脏病发作、中风和过早死亡的风险。我们假设睡眠呼吸暂停患者心血管风险增加与特定的分子机制有关，这些机制诱导血脂升高并导致脂肪肝、糖尿病和动脉粥样硬化。我们建议使用睡眠呼吸暂停小鼠模型来探索这些机制，并确定新的治疗靶点，这可能会改善睡眠呼吸暂停和心血管疾病患者的预后。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) leads to high cardiovascular mortality, which has been attributed to metabolic abnormalities induced by chronic intermittent hypoxia (IH). We have developed a mouse model of chronic IH, which mimics the oxygen profile in human OSA, and have shown that IH causes dyslipidemia, hepatic steatosis and insulin resistance. We have also shown that IH leads to metabolic dysfunction by stimulating a key hepatic enzyme of lipid biosynthesis, stearoyl Coenzyme A desaturase 1 (SCD-1). We accumulated evidence allowing to formulate our main hypothesis that chronic IH causes dyslipidemia and hepatic steatosis by up-regulating SCD-1 via two major pathways, (1) induction of hepatic hypoxia inducible factor 1 (HIF-1) with downstream activation of key factors of lipid biosynthesis, sterol regulatory element binding protein 1c (SREBP-1c), liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPAR3), (2) activation of the sympathetic nervous system (SNS) resulting in increased hepatic glucose output and up-regulation of carbohydrate response element-binding protein ChREBP. In Specific Aim #1 we will examine the role of HIF-1 in metabolic dysfunction during IH. We propose that IH up-regulates SCD-1 via HIF-1 and therefore (A) IH-induced increase in hepatic SCD-1, dyslipidemia and hepatic steatosis will be attenuated in mice with HIF-11 deficient livers; (B) hypoxic up-regulation of SCD-1 will be abolished by HIF-11 deficiency in isolated hepatocytes; (C) constitutive expression of HIF-11 in mouse hepatocytes will induce SCD-1; (D) hypoxia will induce the SCD-1 promoter, this induction will be abolished by HIF-11 deficiency, and constitutively active HIF-11 will be sufficient to drive promoter activity. In Specific Aim #2, we will determine pathways downstream of HIF-1, by which hypoxia induce SCD-1 in cultured hepatocytes. We propose that HIF-1 up-regulates SCD-1 via increased activity of LXR, PPAR3 and SREBP-1c and therefore (A) SCD-1 up-regulation by hypoxia or by constitutive expression of HIF-11 will be attenuated by deficiency of LXR1/2, PPAR3 and SREBP-1c and abolished by the combined deficiency of these transcription factors, (B) induction of the SCD-1 promoter by hypoxia or by constitutive expression of HIF- 11 will be attenuated by deficiency of LXR1/2, PPAR3 and SREBP-1c and abolished by the combined deficiency of these transcription factors. In Specific Aim #3, we will explore the role of ChREBP in up- regulation of hepatic SCD-1 during IH. We propose that IH acts through the SNS to induce ChREBP, which up-regulates SCD-1 leading to dyslipidemia and hepatic steatosis. We hypothesize that (A) induction of hepatic ChREBP by IH will be abolished and up-regulation of SCD-1 will be attenuated by the blockade of the SNS; (B) ChREBP deficiency will attenuate chronic IH-induced increases in hepatic SCD- 1, dyslipidemia and hepatic steatosis. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea increases risk of heart attack, stroke, and premature death. We hypothesize that increased cardiovascular risk in sleep apnea is related to specific molecular mechanisms, which induce elevation of serum lipids and cause fatty liver, diabetes, and atherosclerosis. We propose to use a mouse model of sleep apnea to explore these mechanisms and identify novel therapeutic targets, which may improve outcomes in patients with sleep apnea and the cardiovascular disease.