Division of Pulmonary and Critical Care Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Am J Respir Crit Care Med. 2013 Jul 15;188(2):240-8. doi: 10.1164/rccm.201209-1688OC.
Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown.
To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1).
ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle.
In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue.
HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.
阻塞性睡眠呼吸暂停是血脂异常和动脉粥样硬化的一个风险因素，这些疾病归因于慢性间歇性低氧（CIH）。间歇性低氧抑制脂蛋白清除的关键酶脂蛋白脂酶，并在上皮组织中上调脂蛋白脂酶抑制剂血管生成素样蛋白 4（Angptl4）。睡眠呼吸暂停中 Angptl4 上调的作用和机制尚不清楚。
通过缺氧诱导因子 1（HIF-1）增加脂肪组织 Angptl4，研究 CIH 是否通过增加脂肪组织 Angptl4 导致血脂异常和动脉粥样硬化。
apoE(-/-) 小鼠在接受间歇性低氧或空气暴露的同时，接受 Angptl4 中和抗体或载体治疗 4 周。
在载体处理的小鼠中，低氧增加脂肪组织 Angptl4 水平，抑制脂肪组织脂蛋白脂酶，增加空腹血浆甘油三酯和极低密度脂蛋白胆固醇水平，并增加动脉粥样硬化斑块的大小。抗体消除了 CIH 的作用。在 HIF-1α 敲除等位基因杂合子的小鼠中，没有观察到低氧诱导的血浆空腹甘油三酯和脂肪组织 Angptl4 增加。脂肪组织中 HIF-1α 的转基因过表达导致血脂异常和脂肪组织 Angptl4 水平增加。在培养的脂肪细胞中，组成型表达 HIF-1α 增加 Angptl4 水平，而 siRNA 可消除该作用。最后，在接受减肥手术的肥胖患者中，夜间低氧血症的严重程度预测了皮下脂肪组织中的 Angptl4 水平。
HIF-1 介导的脂肪组织 Angptl4 增加和随后的脂蛋白脂酶失活可能导致睡眠呼吸暂停患者的动脉粥样硬化。
