The Expression of GPIHBP1, an Endothelial Cell Binding Site for Lipoprotein Lipase and Chylomicrons, Is Induced by Peroxisome Proliferator-Activated Receptor-γ

Abstract

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a protein in the lymphocyte antigen 6 (Ly-6) family, plays a key role in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 binds lipoprotein lipase and chylomicrons and is expressed along the luminal surface of microvascular endothelial cells. Lipolysis is known to be regulated by metabolic factors and is controlled at multiple levels, including the number of LPL binding sites on capillaries. Here, we tested the possibility that GPIHBP1 expression could be regulated by dietary perturbations and by peroxisome proliferator-activated receptors (PPARs). Gpihbp1 transcript levels in the heart and in brown and white adipose tissue increased with fasting and returned toward baseline after refeeding. A PPARgamma agonist increased Gpihbp1 expression in adipose tissue, heart, and skeletal muscle, whereas PPARalpha and PPARdelta agonists had no effect. Gpihbp1 was expressed in endothelial cells of embryoid bodies generated from mouse embryonic stem cells, and Gpihbp1 expression in embryoid bodies was up-regulated by a PPARgamma agonist. Sequences upstream from exon 1 of Gpihbp1 contain a strong PPAR binding site, and that site exhibited activity in a luciferase reporter assay. Gpihbp1 transcript levels in brown and white adipose tissue were lower in endothelial cell PPARgamma knockout mice than in littermate control mice, suggesting that PPARgamma regulates Gpihbp1 expression in vivo. We conclude that GPIHBP1 is regulated by dietary factors and by PPARgamma.

Adipose-specific Lipoprotein Lipase Deficiency More Profoundly Affects Brown than White Fat Biology

“…Angplt4 is a PPARregulated gene that is induced by PPAR␥ in adipocytes and PPAR␦ in macrophages (34,35). Although LpL is a source of ligands for PPAR activation (44,45), it is possible that adipose, like the liver, activates PPAR transcription factors using de novo synthesized fatty acids (46). In summary, upon deletion of LpL in adipocytes, we made several observations that provide novel insights into adipose tissue biology.…”

GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins

“…We expected to observe Gpihbp1 expression in endothelial cell lines, but this has not been the case. Davies et al (25) were unable to detect Gpihbp1 expression in rat heart microvascular endothelial cells, human umbilical vein endothelial cells (25), or bovine aortic endothelial cells (unpublished observations). Davies et al (25) also reported that primary endothelial cells from white adipose tissue lost nearly all Gpihbp1 expression after a single passage.…”

“…In embryoid bodies, GPIHBP1 is found in CD31-positive endothelial cells surrounding beating cardiomyocytes (25).…”

“…Peroxisome proliferator-activated receptor (PPAR)a expression levels increase with fasting and PPARa is known to play a key role in energy management during fasting (26). However, Davies et al (25) found no change in Gpihbp1 expression levels when mice were given a PPARa agonist.…”

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

“…Because endothelial cells lose expression of GPIHBP1 when cultured (26), lentiviruses encoding S-protein-tagged mouse GPIHBP1 were transduced into endothelial cells and selected for stable transduction with puromycin as described previously (9). We have previously shown that GPIHBP1 expression levels in lentivirus-transduced RHMVECs are similar to those found in endothelial cells in vivo (9).…”