Obstructive Sleep Apnea (SA) is characterized by recurrent upper airway obstructions during sleep leading to intermittent hypoxia (IH) and sleep fragmentation (SF). SA is a common disease observed in 4% of men and 2% of women in the U.S., which is especially prevalent in obesity affecting more than 50% of obese individuals. SA is an independent risk factor for cardiovascular diseases and is associated with increased incidence of myocardial infarction, stroke, and death. Metabolic disturbances observed in SA, particularly insulin resistance and dyslipidemia, contribute to cardiovascular morbidity. SA is associated with hypercholesterolemia independent of obesity. Potentially both EH and SF may affect metabolic function, and the major purpose of the current proposal is to define the pathways and mechanisms through which SA leads to dysregulation of lipid metabolism. We propose that IH, but not SF without hypoxia, leads to hyperlipidemia and up-regulation of lipid metabolism in the liver. We anticipate that EH will increase plasma lipid levels in both lean and obese individuals. We hypothesize that EH acts by up-regulating lipid biosynthesis in the liver via pathways controlled by sterol regulatory element binding protein 1 (SREBP 1). Finally; we predict that IH will attenuate therapeutic effects of lipid lowering therapy. Our approach is to examine the effects of validated models of IH and SF in lean and obese inbred mice, to explore the functional significance of SREBP pathways using specific transgenic mice, and to examine interactions between EH and lipid lowering treatment. We will employ state-of-the-art techniques of real time PCR, quantitative protein and lipid biochemistry, lipid biosynthesis and lipoprotein clearance in vivo. Specifically, we propose: (1) to examine plasma lipid levels, lipid levels and biosynthesis in the liver, and expression of the enzymes of lipid biosynthesis in the liver of lean mice during IH of different severity and during non-hypoxic SF; (2) to examine the effects of IH on plasma lipids and lipid biosynthesis in the presence of dietary obesity and genetic obesity (db/db and agouti yellow mice); (3) to determine whether the knockout of SREBP pathways alters metabolic responses to EH; (4) to explore interactions between EH and lipid lowering therapy with weight loss and HMG-CoA reductase inhibitors. The proposal will elucidate causative pathways linking SA and dysregulation of lipid metabolism and identify potential intervention for preventing hyperlipidemia and reducing cardiovascular risk in patients with sleep apnea.
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