title: Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
abstract: BACKGROUND
  Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism.
  
  
  RESULTS
  We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia.
  
  
  CONCLUSIONS
  This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bishop
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.forename: Loren
authors.initials: L
authors.lastname: Fong
authors.forename: Kristin I
authors.initials: KI
authors.lastname: Stanford
authors.forename: Jon C
authors.initials: JC
authors.lastname: Gonzales
authors.forename: Erika
authors.initials: E
authors.lastname: Yeh
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Andre
authors.initials: A
authors.lastname: Bensadoun
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Karen S
authors.initials: KS
authors.lastname: Moulton
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D043170:Collagen Type XVIII / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004677:Encephalocele / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D012162:Retinal Degeneration; D012163:Retinal Detachment / Q000097:blood / Q000151:congenital / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D043170:Collagen Type XVIII; D019812:Heparan Sulfate Proteoglycans; D008074:Lipoproteins; D014280:Triglycerides; D008071:Lipoprotein Lipase