Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2010 Nov 10;5(11):e13919. doi: 10.1371/journal.pone.0013919.
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.
脂蛋白脂肪酶（Lpl）作用于外周循环中富含甘油三酯的脂蛋白，释放游离脂肪酸以进行能量代谢或储存。这种必需的酶在脂肪组织、心脏和骨骼肌的实质细胞中合成，并迁移到血管内皮细胞的腔侧，在那里作用于循环脂蛋白。先前的研究表明，Lpl 通过内皮细胞中的肝素硫酸蛋白聚糖固定，但改变内皮细胞肝素硫酸的遗传特性对 Lpl 定位或脂肪分解没有影响。本研究的目的是确定细胞外基质蛋白聚糖是否影响 Lpl 的分布和甘油三酯代谢。
我们检查了胶原 XVIII（Col18）缺陷的突变小鼠，Col18 是一种存在于血管基底膜中的肝素硫酸蛋白聚糖。Col18 的缺失会降低血浆中 Lpl 酶和活性水平，导致轻度空腹高甘油三酯血症和饮食诱导的高乳糜微粒血症。由于血管形式的 Col18 发生无效突变而导致的 Knobloch 综合征患者的血浆 Lpl 质量和活性也低于正常水平，并表现出空腹高甘油三酯血症。
这是第一个证明 Lpl 在内皮细胞腔侧的呈现依赖于基底膜蛋白聚糖的报告，并在缺乏 Col18 的患者中表现出以前未被认识的表型。
