title: Intermittent hypoxia induces hyperlipidemia in lean mice.
abstract: 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-Lep(ob) 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.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Md, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Laura N
authors.initials: LN
authors.lastname: Thorne
authors.forename: Naresh M
authors.initials: NM
authors.lastname: Punjabi
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schwartz
authors.forename: Philip L
authors.initials: PL
authors.lastname: Smith
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Marino
authors.forename: Annabelle
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Walter C
authors.initials: WC
authors.lastname: Hubbard
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis; D006949:Hyperlipidemias / Q000209:etiology*; D000860:Hypoxia / Q000150:complications*; D008055:Lipids / Q000032:analysis / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D051116:Receptors, Scavenger; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D013230:Stearoyl-CoA Desaturase