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Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
- Source :
-
PloS one [PLoS One] 2010 Nov 10; Vol. 5 (11), pp. e13919. Date of Electronic Publication: 2010 Nov 10. - Publication Year :
- 2010
-
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.<br />Methods and Findings: 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.<br />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.
- Subjects :
- Animals
Collagen Type XVIII blood
Collagen Type XVIII genetics
Encephalocele blood
Encephalocele genetics
Encephalocele metabolism
Enzyme-Linked Immunosorbent Assay
Female
Gene Expression Regulation, Enzymologic
Heparan Sulfate Proteoglycans genetics
Heparan Sulfate Proteoglycans metabolism
Humans
Hypertriglyceridemia genetics
Hypertriglyceridemia pathology
Immunohistochemistry
Lipoprotein Lipase blood
Lipoprotein Lipase genetics
Lipoproteins blood
Lipoproteins metabolism
Lipoproteins ultrastructure
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Transmission
Mutation
Retinal Degeneration
Retinal Detachment blood
Retinal Detachment congenital
Retinal Detachment genetics
Retinal Detachment metabolism
Reverse Transcriptase Polymerase Chain Reaction
Triglycerides blood
Triglycerides metabolism
Basement Membrane metabolism
Collagen Type XVIII metabolism
Hypertriglyceridemia metabolism
Lipoprotein Lipase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 5
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21085708
- Full Text :
- https://doi.org/10.1371/journal.pone.0013919