GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons

Abstract

Purpose of review: To summarize recent data indicating that glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) plays a key role in the lipolytic processing of chylomicrons.

Recent findings: Lipoprotein lipase hydrolyses triglycerides in chylomicrons at the luminal surface of the capillaries in heart, adipose tissue, and skeletal muscle. The endothelial cell molecule that facilitates the lipolytic processing of chylomicrons has never been clearly defined. Mice lacking GPIHBP1 manifest chylomicronemia, with plasma triglyceride levels as high as 5000 mg/dl. In wild-type mice, GPIHBP1 is expressed on the luminal surface of capillaries in heart, adipose tissue, and skeletal muscle. Cells transfected with GPIHBP1 bind both chylomicrons and lipoprotein lipase avidly.

Summary: The chylomicronemia in Gpihbp1-deficient mice, the fact that GPIHBP1 is located within the lumen of capillaries, and the fact that GPIHBP1 binds lipoprotein lipase and chylomicrons suggest that GPIHBP1 is a key platform for the lipolytic processing of triglyceride-rich lipoproteins.

Figure 1

Plasma samples after low-speed centrifugation. On the right, lipemic plasma from a Gpihbp1-deficient mouse. The two samples on the left were from unaffected littermates. Reproduced, with permission from Elsevier, from the article by Beigneux and coworkers [37].

Figure 2

Primary structure of mouse GPIHBP1. GPIHBP1 contains an amino-terminal signal peptide, a highly negatively charged domain (with 17 of 25 residues being glutamate or aspartate in the mouse protein), a Ly6 UPAR motif containing multiple cysteines, and a carboxyl-terminal hydrophobic motif triggering the addition of a glycosylphosphatidylinositol (GPI) anchor. A predicted site for N-glycosylation is shaded blue. The PIPLC cleavage site is indicated with a red arrow.

Figure 3

Electron micrographs of negatively stained d < 1.006 g/ml lipoproteins from the plasma of Gpihbp1^−/− and Gpihbp1^+/+ mice, showing larger lipoproteins in Gpihbp1^−/− mice. Reproduced, with permission from Elsevier, from the article by Beigneux and coworkers [37].

Figure 4

GPIHBP1 is located within the lumen of the capillary endothelium of the heart. Confocal microscopy showing the binding of antibodies against CD31 and GPIHBP1 to heart tissue from a Gpihbp1^+/+ mouse. GPIHBP1 staining is particularly prominent on the luminal face of the capillary endothelium. Images were taken with a 100× objective. Reproduced, with permission from Elsevier, from the article by Beigneux and coworkers [37].

Figure 5

Binding of avian LpL (2.5 μg/ml) to pgsA-745 CHO cells transfected with pcDNA3-Gpihbp1 or empty vector, before and after treatment with PIPLC. In parallel experiments, pgsB-761 cells transfected with the Gpihbp1 cDNA also bound 10-fold more LpL than cells transfected with the empty vector. P < 0.0001 for all. Reproduced, with permission from Elsevier, from the article by Beigneux and coworkers [37].

Figure 6

Binding of DiI-labeled chylomicrons (red) to nonpermeabilized CHO-ldlA7 cells that had been transiently transfected with a mouse Gpihbp1 cDNA. Binding was measured at 4°C. GPIHBP1 expression was detected with rabbit anti-GPIHBP1 antiserum and FITC-labeled anti-rabbit IgG (green). Reproduced, with permission from Elsevier, from the article by Beigneux and coworkers [37].

Figure 7

Schematic illustrating the binding of LpL and a chylomicron particle by GPIHPB1 on the surface of a capillary endothelial cell. Of note, the structural domains within GPIHBP1 that bind to LpL and chylomicrons have not yet been defined.

Figure 8

Amino acid alignment showing the relatedness of GPIHBP1 in eight mammalian species. All sequences contain a stretch of negatively charged amino acids (red) at the amino terminus of the protein. Cysteines are in green. Predicted sites for N-glycosylation are shaded blue. The signal peptide is underlined. The carboxyl-terminal transmembrane domain is shaded gray.