Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.

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...

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Main Authors: Joseph R Bishop, Maria Rita Passos-Bueno, Loren Fong, Kristin I Stanford, Jon C Gonzales, Erika Yeh, Stephen G Young, Andre Bensadoun, Joseph L Witztum, Jeffrey D Esko, Karen S Moulton
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2010-11-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC2978080?pdf=render
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spelling doaj-c6874896f581450091c9994b4deff9302020-11-25T02:50:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-11-01511e1391910.1371/journal.pone.0013919Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.Joseph R BishopMaria Rita Passos-BuenoLoren FongKristin I StanfordJon C GonzalesErika YehStephen G YoungAndre BensadounJoseph L WitztumJeffrey D EskoKaren S MoultonLipoprotein 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.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.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.http://europepmc.org/articles/PMC2978080?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Joseph R Bishop
Maria Rita Passos-Bueno
Loren Fong
Kristin I Stanford
Jon C Gonzales
Erika Yeh
Stephen G Young
Andre Bensadoun
Joseph L Witztum
Jeffrey D Esko
Karen S Moulton
spellingShingle Joseph R Bishop
Maria Rita Passos-Bueno
Loren Fong
Kristin I Stanford
Jon C Gonzales
Erika Yeh
Stephen G Young
Andre Bensadoun
Joseph L Witztum
Jeffrey D Esko
Karen S Moulton
Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
PLoS ONE
author_facet Joseph R Bishop
Maria Rita Passos-Bueno
Loren Fong
Kristin I Stanford
Jon C Gonzales
Erika Yeh
Stephen G Young
Andre Bensadoun
Joseph L Witztum
Jeffrey D Esko
Karen S Moulton
author_sort Joseph R Bishop
title Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
title_short Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
title_full Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
title_fullStr Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
title_full_unstemmed Deletion of the basement membrane heparan sulfate proteoglycan type XVIII collagen causes hypertriglyceridemia in mice and humans.
title_sort deletion of the basement membrane heparan sulfate proteoglycan type xviii collagen causes hypertriglyceridemia in mice and humans.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2010-11-01
description 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.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.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.
url http://europepmc.org/articles/PMC2978080?pdf=render
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