title: Regulation of endothelial lipase and systemic HDL cholesterol levels by SREBPs and VEGF-A.
abstract: OBJECTIVE
  Endothelial lipase (EL) regulates HDL cholesterol levels and in inflammatory states, like atherosclerosis, EL expression is increased contributing to low HDL cholesterol. The regulation of EL expression is poorly understood and has mainly been attributed to inflammatory stimuli. As sterol regulatory element binding proteins (SREBPs) are regulators of genes involved in lipid metabolism, we hypothesized that EL is regulated by SREBPs and that EL expression is modified by the SREBP activator vascular endothelial growth factor A (VEGF-A).
  
  
  METHODS
  and results: Quantitative PCR and Western blot results demonstrated that starvation increased EL expression in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). Also, 25-hydroxycholesterol (25HC), an inhibitor of SREBP activation inhibited EL expression. With siRNA-mediated inhibition of SREBPs the effect of starvation was shown to be SREBP-2 dependent. VEGF-A decreased EL expression in both endothelial cell lines used, most likely via inhibition of SREBP-2 binding determined by chromatin immunoprecipitation (ChIP). Furthermore, in atherosclerosis prone LDLR(-/-)ApoB(100/100) mice, systemic adenoviral gene transfer with human VEGF-A decreased EL mRNA in peripheral tissues and increased plasma HDL cholesterol.
  
  
  CONCLUSIONS
  These results identify SREBPs as novel regulators of EL expression. VEGF-A as an endogenous EL inhibitor could be therapeutically relevant in atherosclerosis by increasing systemic HDL cholesterol levels.
authors.affiliation: University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, Neulaniementie 2, FIN-70211 Kuopio, Finland.
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Kivelä
authors.forename: Marike H
authors.initials: MH
authors.lastname: Dijkstra
authors.forename: Suvi E
authors.initials: SE
authors.lastname: Heinonen
authors.forename: Erika
authors.initials: E
authors.lastname: Gurzeler
authors.forename: Suvi
authors.initials: S
authors.lastname: Jauhiainen
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D053299:Apolipoprotein B-100 / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics; D001665:Binding Sites; D015153:Blotting, Western; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D053299:Apolipoprotein B-100; D008076:Cholesterol, HDL; D006888:Hydroxycholesterols; D012333:RNA, Messenger; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C007997:25-hydroxycholesterol; C410382:LIPG protein, human; D008049:Lipase; C498741:Lipg protein, mouse