Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea

Delayed lipoprotein clearance is associated with atherosclerosis. This study examined whether chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnoea (OSA), can lead to hyperlipidaemia by inhibiting clearance of triglyceride rich lipoproteins (TRLP). Male C57BL/6J mice on high-cholesterol diet were exposed to 4 weeks of CIH or chronic intermittent air (control). FIO2 was decreased to 6.5 once per minute during the 12 h light phase in the CIH group. After the exposure, we measured fasting lipid profile. TRLP clearance was assessed by oral gavage of retinyl palmitate followed by serum retinyl esters (REs) measurements at 0, 1, 2, 4, 10, and 24 h. Activity of lipoprotein lipase (LpL), a key enzyme of lipoprotein clearance, and levels of angiopoietin-like protein 4 (Angptl4), a potent inhibitor of the LpL activity, were determined in the epididymal fat pads, skeletal muscles, and heart. Chronic intermittent hypoxia induced significant increases in levels of total cholesterol and triglycerides, which occurred in TRLP and LDL fractions (P 0.05 for each comparison). Compared with control mice, animals exposed to CIH showed increases in REs throughout first 10 h after oral gavage of retinyl palmitate (P 0.05), indicating that CIH inhibited TRLP clearance. CIH induced a 5-fold decrease in LpL activity (P 0.01) and an 80 increase in Angptl4 mRNA and protein levels in the epididymal fat, but not in the skeletal muscle or heart. CIH decreases TRLP clearance and inhibits LpL activity in adipose tissue, which may contribute to atherogenesis observed in OSA.

Mid-Atlantic Nutrition Obesity Research Center (NORC) (NIH) [P30 DK072488]

MidAtlantic Nutrition Obesity Research Center (NORC) (NIH)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [200032/2009-7]

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)

Fundacao Zerbini, Brazil

Fundacao Zerbini, Brazil

National Sleep Foundation/American Lung Association [SF-78568-N]

National Sleep Foundation/American Lung Association

NIH [HL07534, R01 HL80105, 5P50HL084945]

NIH

German Research Foundation (DFG) [RE 2842/1-1]

German Research Foundation (DFG)

Swedish Medical Research Fund

Swedish Medical Research Fund [12 203]

Swedish Heart and Lung Foundation

Swedish Heart and Lung Foundation [20090578]

American Heart Association

American Heart Association [10GRNT3360001]

United States Israel Binational Science Foundation

United States Israel Binational Science Foundation [2005265]