Multimerization of Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1) and Familial Chylomicronemia from a Serine-to-Cysteine Substitution in GPIHBP1 Ly6 Domain

Plengpanich, Wanee; Young, Stephen G.; Khovidhunkit, Weerapan; Bensadoun, André; Karnman, Hirankorn; Ploug, Michael; Gårdsvoll, Henrik; Leung, Calvin S.; Adeyo, Oludotun; Larsson, Mikael; Muanpetch, Suwanna; Charoen, Supannika; Fong, Loren G.; Niramitmahapanya, Sathit; Beigneux, Anne P.

doi:10.1074/jbc.m114.558528

Cited by 46 publications

(69 citation statements)

References 37 publications

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“…Fab′ fragments were prepared with immobilized papain and Fc fragments removed with Protein LU domain is primarily responsible for high-affinity binding of LPL, while the acidic domain augments the interaction and promotes an initial interaction complex between LPL and GPIHBP1 (6,11). A variety of missense mutations in GPIHBP1's LU domain have been identified in patients with chylomicronemia (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), and all of those abolish the ability of GPIHBP1 to bind LPL (6). Most of these mutations interfere with the formation of disulfide bonds in the LU domain, leading to disulfide-linked dimers and multimers (23).…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

“…We used cell-free and cell-based LPL-GPIHBP1 binding assays (18,23,31,33) to test the ability of three LPLspecific mAbs (5D2, 88B8, 57A5) (29,30) to block the binding of hLPL to GPIHBP1. In the cell-free assay, we incubated GPIHBP1, LPL, and an LPL-specific mAb with agarose beads that had been coated with a GPIHBP1-specific mAb (11A12).…”

Section: Testing the Ability Of Lpl-specific Mabs To Block The Bindinmentioning

confidence: 99%

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An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

Allan

Larsson

et al. 2016

Journal of Lipid Research

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For more than 50 years, it has been known that LPL, a triglyceride hydrolase secreted by myocytes and adipocytes, is crucial for the intravascular processing of triglyceriderich lipoproteins (TRLs) (1-3). For most of that time, it was assumed that LPL was attached to the heparan-sulfate proteoglycans along the lumen of blood vessels (4), but how LPL reached the lumen of blood vessels was a stubborn mystery. Within the past few years, that mystery has been solved (5, 6). Glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), a GPI-anchored protein of capillary endothelial cells, picks up freshly secreted LPL within the interstitial spaces and shuttles it across endothelial cells to the capillary lumen (7,8). In the absence of GPIHBP1, LPL remains in the interstitial spaces and never reaches the capillary lumen, resulting in an accumulation of plasma TRLs and extremely high plasma triglyceride levels ("chylomicronemia") (8). Recent studies showed that GPIHBP1 (and GPIHBP1-bound LPL) are also crucial for the margination of TRLs along the capillary lumen, allowing triglyceride hydrolysis to proceed (9).GPIHBP1 has two main structural features-an aminoterminal acidic domain and a cysteine-rich three-fingered "LU domain" (7, 10). Recent studies have shown that the Abstract LPL contains two principal domains: an aminoterminal catalytic domain (residues 1-297) and a carboxylterminal domain (residues 298-448) that is important for binding lipids and binding glycosylphosphatidylinositolanchored high density lipoprotein binding protein 1 (GPIHBP1) (an endothelial cell protein that shuttles LPL to the capillary lumen). The LPL sequences required for GPIHBP1 binding have not been examined in detail, but one study suggested that sequences near LPL's carboxyl terminus (residues 403-438) were crucial. Here, we tested the ability of LPLspecific monoclonal antibodies (mAbs) to block the binding of LPL to GPIHBP1. One antibody, 88B8, abolished LPL binding to GPIHBP1. Consistent with those results, antibody 88B8 could not bind to GPIHBP1-bound LPL on cultured cells. Antibody 88B8 bound poorly to LPL proteins with amino acid substitutions that interfered with GPIHBP1 binding (e.g., C418Y, E421K). However, the sequences near LPL's carboxyl terminus (residues 403-438) were not sufficient for 88B8 binding; upstream sequences (residues 298-400) were also required. Additional studies showed that these same sequences are required for LPL binding to GPI-HBP1. In conclusion, we identified an LPL mAb that binds to LPL's GPIHBP1-binding domain. The binding of both antibody 88B8 and GPIHBP1 to LPL depends on large segments of LPL's carboxyl-terminal domain.

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Section: Monoclonal Antibodiesmentioning

confidence: 99%

Section: Testing the Ability Of Lpl-specific Mabs To Block The Bindinmentioning

confidence: 99%

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

Allan

Larsson

et al. 2016

Journal of Lipid Research

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“…We also examined de-identified archived plasma samples from patients with loss-of-function mutations in GPIHBP1 . 1, 3, 13 Those samples had been sent to UCLA without identifiers; 1 accordingly, studies of those plasma samples were deemed exempt from institutional review board approval.…”

Section: Methodsmentioning

confidence: 99%

An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum

Miyashita

Fukamachi

Nagao

et al. 2018

Journal of Clinical Lipidology

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BACKGROUND GPIHBP1, a glycosylphosphatidylinositol (GPI)-anchored protein of capillary endothelial cells, transports lipoprotein lipase to the capillary lumen and is essential for the lipolytic processing of triglyceride-rich lipoproteins. OBJECTIVE Because some GPI-anchored proteins have been detected in plasma, we tested whether GPIHBP1 is present in human blood, and whether GPIHBP1 deficiency or a history of cardiovascular disease affected GPIHBP1 circulating levels. METHODS We developed two monoclonal antibodies against GPIHBP1and used the antibodies to established a sandwich ELISA to measure GPIHBP1 levels in human blood. RESULTS The GPIHBP1 ELISA was linear in the 8–500 pg/ml range and allowed the quantification of GPIHBP1 in serum and in pre- and post-heparin plasma (including lipemic samples). GPIHBP1 was undetectable in the plasma of subjects with null mutations in GPIHBP1. Serum GPIHBP1 median levels were 849 pg/ml (range: 740–1014) in healthy volunteers (n = 28) and 1087 pg/ml (range: 877–1371) in patients with a history of cardiovascular or metabolic disease (n = 415). There was an extremely small inverse correlation between GPIHBP1 and triglyceride levels (r = 0.109; P <0.0275). GPIHBP1 levels tended to be slightly higher in patients who had a major cardiovascular event after revascularization. CONCLUSION We developed an ELISA for quantifying GPIHBP1 in human blood. This assay will be useful to identify patients with GPIHBP1 deficiency and patients with GPIHBP1 autoantibodies. The potential of plasma GPIHBP1 as a biomarker for metabolic or cardiovascular disease is yet questionable but needs additional testing.

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“…The second finger of GPIHBP1's Ly6 domain is particularly important for LPL binding (4,23). A variety of amino acid substitutions within the second finger abolish GPIHBP1's capacity to bind LPL, in some cases by interfering with the proper formation of disulfide bonds (11,23,24). Mutations in W109 in human GPIHBP1 abolish the capacity of GPIHBP1 to bind LPL and do so without disrupting disulfide bond formation, suggesting that W109 is directly involved in LPL-GPIHBP1 interactions (24).…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of GPIHBP1, LPL's triglyceride hydrolase domain unfolds, resulting in a rapid decline in catalytic activity (4). GPIHBP1 and LPL are equally important for intravascular lipolysis; a deficiency of either protein markedly impairs intravascular triglyceride hydrolysis and leads to severe hypertriglyceridemia (chylomicronemia) (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The importance of GPIHBP1 and LPL for plasma triglyceride metabolism in mammals has been underscored by human genetics; specific missense mutations in either protein can abolish LPL-GPIHBP1 interactions, resulting in reduced delivery of LPL to the capillary lumen, impaired TRL processing, and severe hypertriglyceridemia (6,7,(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

He¹,

Jung

et al. 2017

JCI Insight

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Multimerization of Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1) and Familial Chylomicronemia from a Serine-to-Cysteine Substitution in GPIHBP1 Ly6 Domain

Cited by 46 publications

References 37 publications

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum

Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

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