Sleep Apnea and Dysregulation of Lipid Metabolism

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）引起的代谢异常。我们开发了一种小鼠模型 慢性IH，模仿人类OSA中的氧分布，并已表明IH导致 血脂异常、肝脂肪变性和胰岛素抵抗。我们还表明，IH导致代谢 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引起的功能障碍 （SCD-1）。我们积累的证据使我们能够提出我们的主要假设，即慢性IH导致 通过上调SCD-1通过两个主要途径，（1）诱导 肝缺氧诱导因子-1与下游脂质关键因子激活 生物合成、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？），（2）激活交感神经 神经系统（SNS），导致肝葡萄糖输出增加和 碳水化合物反应元件结合蛋白ChREBP。在具体目标#1中，我们将检查 HIF-1在IH期间代谢功能障碍中的作用。我们认为IH通过HIF-1上调SCD-1， 因此（A）IH诱导的肝SCD-1增加、血脂异常和肝脂肪变性将减弱 在具有HIF-1缺陷肝脏的小鼠中;（B）缺氧上调的SCD-1将被HIF-1消除。 缺乏分离的肝细胞;（C）在小鼠肝细胞中HIF-1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-1缺陷所消除， 而组成型活性HIF-1 <$将足以驱动启动子活性。在具体目标#2中，我们将 确定HIF-1的下游途径，通过该途径缺氧诱导培养的肝细胞中的SCD-1。 我们认为HIF-1通过增加LXR、PPAR γ和SREBP-1c的活性上调SCD-1， 因此，（A）缺氧或HIF-1的组成型表达引起的SCD-1上调将被减弱， LXR、PPAR和SREBP-1c的缺乏，并被这些的联合缺乏所消除 转录因子，（B）通过缺氧或通过HIF-1的组成型表达诱导SCD-1启动子。 1 <$将因LXR <$/<$、PPAR <$和SREBP-1c的缺乏而减弱，并被联合 缺乏这些转录因子。在具体目标#3中，我们将探讨ChREBP在上调中的作用- IH期间肝SCD-1的调节。我们认为IH通过SNS诱导ChREBP， 其上调SCD-1，导致血脂异常和肝脂肪变性。我们假设（A） IH对肝ChREBP的诱导作用将被消除，SCD-1的上调将被抑制。 （B）ChREBP缺乏将减弱慢性IH诱导的肝SCD增加。 1、血脂异常与肝脂肪变性。

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 (PPAR¿), (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-1¿ deficient livers; (B) hypoxic up-regulation of SCD-1 will be abolished by HIF-1¿ deficiency in isolated hepatocytes; (C) constitutive expression of HIF-1¿ in mouse hepatocytes will induce SCD-1; (D) hypoxia will induce the SCD-1 promoter, this induction will be abolished by HIF-1¿ deficiency, and constitutively active HIF-1¿ 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, PPAR¿ and SREBP-1c and therefore (A) SCD-1 up-regulation by hypoxia or by constitutive expression of HIF-1¿ will be attenuated by deficiency of LXR¿/¿, PPAR¿ 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- 1¿ will be attenuated by deficiency of LXR¿/¿, PPAR¿ 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.