Chylomicronemia With Low Postheparin Lipoprotein Lipase Levels in the Setting of GPIHBP1 Defects

Abstract

Background-Recent studies in mice have established that an endothelial cell protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), is essential for the lipolytic processing of triglyceride-rich lipoproteins. Methods and Results-We report the discovery of a homozygous missense mutation in GPIHBP1 in a young boy with severe chylomicronemia. The mutation, p.C65Y, replaces a conserved cysteine in the GPIHBP1 lymphocyte antigen 6 domain with a tyrosine and is predicted to perturb protein structure by interfering with the formation of a disulfide bond. Studies with transfected Chinese hamster ovary cells showed that GPIHBP1-C65Y reaches the cell surface but has lost the ability to bind lipoprotein lipase (LPL). When the GPIHBP1-C65Y homozygote was given an intravenous bolus of heparin, only trace amounts of LPL entered the plasma. We also observed very low levels of LPL in the postheparin plasma of a subject with chylomicronemia who was homozygous for a different GPIHBP1 mutation (p.Q115P). When the GPIHBP1-Q115P homozygote was given a 6-hour infusion of heparin, a significant amount of LPL appeared in the plasma, resulting in a fall in the plasma triglyceride levels from 1780 to 120 mg/dL. Conclusions-We identified a novel GPIHBP1 missense mutation (p.C65Y) associated with defective LPL binding in a young boy with severe chylomicronemia. We also show that homozygosity for the C65Y or Q115P mutations is associated with low levels of LPL in the postheparin plasma, demonstrating that GPIHBP1 is important for plasma triglyceride metabolism in humans. (Circ Cardiovasc Genet. 2010;3:169-178.)

GPIHBP1, an endothelial cell transporter for lipoprotein lipase

“…In embryoid Whether the "fasting/refeeding regulation" of GPI-HBP1 is physiologically important is uncertain. The changes in expression with fasting and refeeding were twofold or less, and studies of humans suggest that half-normal amounts of GPIHBP1 have no signifi cant impact on triglyceride levels ( 25,27 ). Also, at this point, we caution that all data on GPIHBP1 regulation is derived from the mouse; whether GPIHBP1 expression in humans is regulated in a similar fashion is unknown.…”

“…11 ) ( 26 ). A homozygous C65Y mutation in GPIHBP1 was identifi ed in a 3-year-old boy with chylomicronemia ( 25 ). The proband had no mutations in LPL , LMF1 , APOC2 , or APOA5 ( 25 ).…”

“…We now know that glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1, (GPIHBP1), a GPI-anchored protein of capillary endothelial cells, binds LPL in the subendothelial spaces and transports it to the capillary lumen ( 24 ). The binding of LPL to GPIHBP1 is highly specifi c; even single amino acid substitutions in GPIHBP1 or LPL can abolish their interaction, leading to impaired lipolysis and hypertriglyceridemia (25)(26)(27)(28)(29). We discuss each of these topics in this review.…”

Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1

“…This transport is carried out by GPIHBP1, which binds LPL secreted by parenchymal cells and transcytotically transports it to the capillary lumen (9 -11). In GPIHBP1-deficient mice, LPL accumulates in the interstitial space and is absent from the capillary lumen, resulting in a dramatic reduction in triglyceride processing and severely elevated plasma triglyceride levels (9,10,(12)(13)(14)(15)(16)(17)(18).…”

Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1

“…GPIHBP1 missense mutations were recently shown to cause chylomicronemia in humans (12)(13)(14). In each case, these mutations abolished GPIHBP1's capacity to bind LPL.…”