Published online before print August 25, 2005, doi: 10.1161/01.RES.0000183879.60089.a9
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© 2005 American Heart Association, Inc.
Integrative Physiology |
Intermittent Hypoxia Induces Hyperlipidemia in Lean Mice
From the Department of Medicine, Divisions of Pulmonary and Critical Care Medicine (J.L., L.N.T., N.M.P., A.R.S., P.L.S., V.Y.P.), Endocrinology and Metabolism (R.L.M., A.R.), and Allergy and Clinical Immunology (W.C.H.), Johns Hopkins University, Baltimore, Md; and the Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine (C.-K.S., C.P.O.), University of Pittsburgh School of Medicine, Pennsylvania.
Correspondence to Vsevolod Y. Polotsky, MD, PhD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Cir, Baltimore, MD 21224. E-mail vpolots1{at}jhmi.edu
Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lepob mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl–coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.
Key Words: obstructive sleep apnea • cholesterol homeostasis • lipids • hypoxia • mouse • gene expression
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