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This article is available online at http://www.jlr.org signifi cant cardiovascular morbidity and mortality (2)(3)(4). Several lines of evidence demonstrated that OSA is associated with dyslipidemia and accelerated atherosclerosis ( 5-12 ). A randomized, placebo-controlled clinical trial of continuous positive airway pressure (CPAP) has shown that OSA treatment with CPAP markedly reduces postprandial hyperlipidemia ( 13 ). Postprandial hypertriglyceridemia may confer risk for myocardial infarction, isch emic heart disease, stroke, and death (14)(15)(16)(17)(18)(19)(20). Therefore, it is conceivable that postprandial hyperlipidemia contributes to the cardiovascular risk of OSA. The pathogenesis of postprandial hyperlipidemia in OSA is unknown.We developed a mouse model of CIH, which mimics oxyhemoglobin desaturations in patients with OSA ( 21-23 ). Using this model, we have recently shown that CIH impairs chylomicron clearance in mice and inhibits a key enzyme of triglyceride-rich lipoprotein clearance, lipoprotein lipase (LPL), in adipose tissue ( 24 ). CIH also upregulated a potent LPL inhibitor, adipose angiopoietin-like protein 4 (Angptl4) ( 24 ). However, the effect of CIH on triglyceride (TG) uptake by adipose tissue has not been explored; contribution of other organs and tissues to lipoprotein clearance during CIH is unknown. Finally, the role of Angptl4 in CIH-induced metabolic dysfunction has not been determined.We hypothesized that CIH impairs TG uptake by adipose tissue depots and other organs and tissues via Angptl4. We exposed C57BL/6J mice to CIH for four weeks while treating them with Angptl4-neutralizing antibodies (Ab) or placebo (vehicle solution) and examined plasma clearance and tissue uptake of [H 3 ]triolein-Intralipid. Abstract Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL)activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4). We hypothesize that CIH inhibits triglyceride (TG) uptake via Angptl4 and that an anti-Angptl4-neutralizing antibody would abolish the effects of CIH. Male C57BL/6J mice were exposed to four weeks of CIH or intermittent air (IA) while treated with Ab (30 mg/kg ip once a week). TG clearance was assessed by [H 3 ]triolein administration retroorbitally. CIH delayed TG clearance and suppressed TG uptake and LPL activity in all white adipose tissue depots, brown adipose tissue, and lungs, whereas heart, liver, and spleen were not affected. CD146+ CD11b ؊ pulmonary microvascular endothelial cells were responsible for TG uptake in the lungs and its inhibition by CIH. Antibody to Angptl4 decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. The antibody reversed the effects of CIH on LPL in adipose tissue and lungs. In conclusion, CIH inactivates LPL by upregulating Angptl4, but inhibition of TG uptake occurs predominantly via an A...

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