title: Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice.
abstract: Obstructive sleep apnea (OSA) induces intermittent hypoxia (IH) during sleep and is associated with elevated triglycerides (TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO(2) = 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dose-dependently increased plasma TG, with levels peaking at FiO(2) = 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO(2) = 0.10. Plasma catecholamines also increased inversely with FiO(2). Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO(2) = 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [(3)H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-γ, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. jjun2@jhmi.edu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Jun
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Shin
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Yao
authors.forename: Shannon
authors.initials: S
authors.lastname: Bevans-Fonti
authors.forename: James
authors.initials: J
authors.lastname: Poole
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Drager
authors.forename: Vsevolod Y
authors.initials: VY
authors.lastname: Polotsky
mesh_terms: D000208:Acute Disease; D000818:Animals; D004041:Dietary Fats / Q000493:pharmacokinetics; D004655:Emulsions / Q000008:administration & dosage / Q000493:pharmacokinetics; D005217:Fat Emulsions, Intravenous / Q000493:pharmacokinetics; D015228:Hypertriglyceridemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D000860:Hypoxia / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000494:pharmacology; D010743:Phospholipids / Q000008:administration & dosage / Q000493:pharmacokinetics; D013024:Soybean Oil / Q000008:administration & dosage / Q000493:pharmacokinetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*; D014304:Triolein / Q000008:administration & dosage / Q000493:pharmacokinetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D004655:Emulsions; D005217:Fat Emulsions, Intravenous; D010743:Phospholipids; D014280:Triglycerides; C545823:soybean oil, phospholipid emulsion; D014304:Triolein; D013024:Soybean Oil; D010100:Oxygen