Key result
In humans with Knobloch syndrome, a null mutation in the vascular form of collagen XVIII caused fasting hypertriglyceridemia and significantly decreased plasma lipoprotein lipase mass and activity compared to unaffected family members.
Why the study?
Does deficiency of collagen XVIII cause hypertriglyceridemia and alter lipoprotein lipase distribution in mice and humans?
Observational (n=25)
No
Does deficiency of collagen XVIII cause hypertriglyceridemia and alter lipoprotein lipase distribution in mice and humans?
Deletion of the basement membrane proteoglycan collagen XVIII reduces luminal presentation of lipoprotein lipase, leading to hypertriglyceridemia in both mice and humans with Knobloch Syndrome.
Collagen XVIII deficiency may underlie hypertriglyceridemia in Knobloch syndrome; leaves open relevance to common dyslipidemias or therapeutic targeting.
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. 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. 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.
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Bishop et al. (2010) conducted an observational in Knobloch Syndrome (COL18A1 mutation) / Hypertriglyceridemia (n=25). COL18A1 null mutation (Knobloch syndrome) vs. Unaffected family members (normal controls and heterozygotes) was evaluated on Fasting plasma triglycerides (p=<0.05). In humans with Knobloch syndrome, a null mutation in the vascular form of collagen XVIII caused fasting hypertriglyceridemia and significantly decreased plasma lipoprotein lipase mass and activity compared to unaffected family members.
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