Sleep Apnea and Dysregulation of Lipid Metabolism

阻塞性睡眠呼吸暂停(OSA)导致较高的心血管死亡率，这被归因于 慢性间歇性缺氧(IH)引起的代谢异常。我们已经研制出一种小鼠模型 它模拟了人类阻塞性睡眠呼吸暂停低氧血症的氧气分布，并已表明高血压导致 血脂异常、肝脏脂肪变性和胰岛素抵抗。我们还表明，IH导致新陈代谢 刺激肝脏脂质生物合成的关键酶硬脂酰辅酶A去饱和酶1所致的功能障碍 (SCD-1)。我们积累的证据使我们能够阐明我们的主要假设，即慢性高血压导致 通过两条主要途径上调SCD-1引起的血脂异常和肝脏脂肪变性，(1)诱导 肝脏缺氧诱导因子-1与脂质关键因子的下游激活 生物合成、固醇调节元件结合蛋白1c(SREBP-1c)、肝X受体(LXRs)和 过氧化物酶体增殖物激活受体γ，(2)交感神经的激活 神经系统(SNS)导致肝脏葡萄糖输出量增加和 碳水化合物反应元件结合蛋白ChREBP。在具体目标#1中，我们将研究 缺氧诱导因子-1在高血压病代谢紊乱中的作用。我们认为IH通过HIF-1上调SCD-1，并 因此，(A)IH诱导的肝脏SCD-1升高、血脂异常和肝脏脂肪变性将得到缓解 在HIF-1缺乏肝脏的小鼠中；(B)缺氧时SCD-1的上调将被HIF-1取消 (C)HIF-1在小鼠肝细胞中的结构性表达将诱导 (D)缺氧会诱导SCD-1启动子，这种诱导作用将被HIF-1β缺乏所取消， 而结构性活性的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下游低氧诱导培养肝细胞SCD-1的途径。 我们认为，HIF-1通过增加LXR、PPAR和SREBP-1c的活性上调SCD-1，并 因此，(A)缺氧或HIF-1结构性表达对SCD-1的上调作用将被以下因素减弱 LXR、PPAR和SREBP-1c的缺乏及其联合应用 转录因子，(B)通过缺氧或HIF-1的结构性表达诱导SCD-1启动子- LXR、PPAR和SREBP-1c的缺乏将使其减弱，并被联合应用所取消 这些转录因子的缺失。在具体目标3中，我们将探索ChREBP在UP- 肝组织SCD-1在IH过程中的调节我们认为IH通过SNS诱导CHREBP， 它上调SCD-1，导致血脂异常和肝脏脂肪变性。我们假设(A) 将取消IH诱导的肝脏ChREBP，并减弱SCD-1的上调 阻断SNS；(B)ChREBP缺乏将减轻慢性IH诱导的肝脏SCD-1增加。 1、血脂异常、肝脏脂肪变性。

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.