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Journal of Lipid Research, Vol. 50, 2421-2429, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4

William K. Sonnenburg^1,3,*, Daiguan Yu^1,*, E-Chiang Lee^*, Wei Xiong^*, Gennady Gololobov^*, Billie Key^*, Jason Gay, Nat Wilganowski, Yi Hu, Sharon Zhao, Matthias Schneider, Zhi-Ming Ding, Brian P. Zambrowicz^*,,, Greg Landes^2,*, David R. Powell and Urvi Desai^3,

^* Departments of Biotherapeutics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381
Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381
Molecular Biology, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381

³ To whom correspondence should be addressed. e-mail: WSonnenburg{at}lexpharma.com or UDesai{at}lexpharma.com

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.

Supplementary key words glycosylphosphatidylinositol-anchored HDL-binding protein • knockout mice • monoclonal antibodies • hypertriglyceridemia • chylomicronemia • ANGPTL4-neutralizing monoclonal antibody • ANGPTL3-neutralizing monoclonal antibody

Abbreviations: ANGPTL, angiopoietin-like; APOC2, apolipoprotein CII; APOA5, apolipoprotein AV; APOC1, apolipoprotein CI; APOC3, apolipoprotein CIII; CI, confidence interval; CM, chylomicrons; DGGR, 1,2-O-dilauryl-rac-glycero-3-glutaric acid – (6'-methylresorufin) ester; KLH, keyhole limpet hemocyanin; GPI, glycosylphosphatidylinositol; GPIHBP1, GPI-anchored HDL-binding protein; Ly6, lymphocyte antigen 6; RFU, relative fluorescence units; TG, triglyceride; –/–, homozygous null; +/–, heterozygous null; +/+, wild-type

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