title: Increased plasma sphingosine-1-phosphate in obese individuals and its capacity to increase the expression of plasminogen activator inhibitor-1 in adipocytes.
abstract: OBJECTIVE
  Concentrations of plasminogen activator inhibitor-1 (PAI-1) are increased in obese individuals. One source of PAI-1 is adipocytes. Hypoxia develops within adipose tissue as it expands, presumably contributing to increased levels of sphingosine-1-phosphate (S1P). S1P is a breakdown product of sphingosine, ubiquitous in cell membranes. We have shown previously that S1P increases the expression of PAI-1 in human liver-derived cell line. In the present study, we aimed to determine whether hypoxia induces S1P in adipocytes, thereby potentially contributing to an increase in PAI-1 and hence constraints on fibrinolysis associated with obesity.
  
  
  METHODS
  Mouse 3T3-L1 adipocytes were exposed to CoCl2 to simulate hypoxia. Assays were performed for PAI-1 mRNA (quantitative PCR) and S1P (high-performance liquid chromatography).
  
  
  RESULTS
  The physiologic concentration of S1P increased PAI-1 mRNA expression. The S1P2 receptor antagonist attenuated the increase in PAI-1. Adipocytes expressed sphingosine kinase 1/2 (SPHK1/2) and S1P lyase, key enzymes involved in S1P production and degradation. Hypoxia increased SPHK activity and decreased S1P lyase mRNA. Hypoxia reduced cytosolic sphingosine and increased S1P release into conditioned medium. Inhibitors of ABCA1 and ABCC1 reduced the release of S1P into conditioned media. In obese patients with uncomplicated dyslipidemia and hypertension, plasma S1P was increased compared with that in nonobese and lean individuals.
  
  
  CONCLUSIONS
  Hypoxia in adipose tissue of obesity can promote elaboration of S1P that binds to S1P2 receptors in an autocrine or a paracrine manner. S1P potentially contributes toward increased expression of PAI-1 and consequent constraints on fibrinolysis. S1P production and extracellular transport provide an attractive target for therapy to attenuate impaired fibrinolysis associated with obesity.
authors.affiliation: aDepartment of Molecular and Cellular Pathobiology and Therapeutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya bDepartment of Clinical Laboratory, The University of Tokyo Hospital, Tokyo cDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan dDepartment of Medicine, University of Vermont, Colchester, Vermont, USA.
authors.forename: Shiori
authors.initials: S
authors.lastname: Ito
authors.forename: Soichiro
authors.initials: S
authors.lastname: Iwaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Koike
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yuda
authors.forename: Ayako
authors.initials: A
authors.lastname: Nagasaki
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Ohkawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.forename: Tomoo
authors.initials: T
authors.lastname: Furumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
mesh_terms: D041721:3T3-L1 Cells; D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000368:Aged; D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015992:Body Mass Index; D015687:Cell Hypoxia; D017077:Culture Media, Conditioned; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009765:Obesity / Q000097:blood* / Q000175:diagnosis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D000081025:Sphingosine-1-Phosphate Receptors; D013997:Time Factors; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000446:Aldehyde-Lyases; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C577833:Abca1 protein, mouse; C051321:SERPINE1 protein, human; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; C022649:sphingosine 1-phosphate lyase (aldolase); C421109:multidrug resistance-associated protein 1