title: GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4.
abstract: 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.
authors: Department of Biotherapeutics, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA.
authors: William K
authors: WK
authors: Sonnenburg
authors: Daiguan
authors: D
authors: Yu
authors: E-Chiang
authors: EC
authors: Lee
authors: Wei
authors: W
authors: Xiong
authors: Gennady
authors: G
authors: Gololobov
authors: Billie
authors: B
authors: Key
authors: Jason
authors: J
authors: Gay
authors: Nat
authors: N
authors: Wilganowski
authors: Yi
authors: Y
authors: Hu
authors: Sharon
authors: S
authors: Zhao
authors: Matthias
authors: M
authors: Schneider
authors: Zhi-Ming
authors: ZM
authors: Ding
authors: Brian P
authors: BP
authors: Zambrowicz
authors: Greg
authors: G
authors: Landes
authors: David R
authors: DR
authors: Powell
authors: Urvi
authors: U
authors: Desai
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D004795:Enzyme Stability; D006801:Humans; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018110:Receptors, Lipoprotein / Q000172:deficiency / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C479896:ANGPTL3 protein, human; C474772:ANGPTL4 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; C407088:Angptl4 protein, mouse; D002352:Carrier Proteins; C472779:GPI-HBP1 protein, mouse; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D008071:Lipoprotein Lipase