文章基本信息

标题：GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4
本地全文：下载
作者：William K. Sonnenburg ; Daiguan Yu ; E-Chiang Lee 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2009
卷号：50
期号：12
页码：2421-2429
DOI：10.1194/jlr.M900145-JLR200
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) binds both LPL and chylomicrons, suggesting that GPIHBP1 is a platform for LPL-dependent processing of triglyceride (TG)-rich lipoproteins. Here, we investigated whether GPIHBP1 affects LPL activity in the absence and presence of LPL inhibitors angiopoietin-like (ANGPTL)3 and ANGPTL4. Like heparin, GPIHBP1 stabilized but did not activate LPL. ANGPTL4 potently inhibited nonstabilized LPL as well as heparin-stabilized LPL but not GPIHBP1-stabilized LPL. Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. ANGPTL3 also inhibited heparin-stabilized LPL but with less potency than nonstabilized LPL. Consistent with these in vitro findings, fasting serum TGs of Angptl4 ^−/−/ Gpihbp1 ^−/− mice were lower than those of Gpihbp1 ^−/− mice and approached those of wild-type littermates. In contrast, serum TGs of Angptl3 ^−/−/ Gpihbp1 ^−/− mice were only slightly lower than those of Gpihbp1 ^−/− mice. Treating Gpihbp1 ^−/− mice with ANGPTL4- or ANGPTL3-neutralizing antibodies recapitulated the double knockout phenotypes. These data suggest that GPIHBP1 functions as an LPL stabilizer. Moreover, therapeutic agents that prevent LPL inhibition by ANGPTL4 or, to a lesser extent, ANGPTL3, may benefit individuals with hyperlipidemia caused by gene mutations associated with decreased LPL stability.
关键词：glycosylphosphatidylinositol-anchored HDL-binding protein ; knockout mice ; monoclonal antibodies ; hypertriglyceridemia ; chylomicronemia ; ANGPTL4-neutralizing monoclonal antibody ; ANGPTL3-neutralizing monoclonal antibody