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

Abstract

GPIHBP1, a small glycosylphosphatidylinositolanchored glycoprotein, is required for the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 knockout mice exhibit chylomicronemia, even on a low-fat diet, with plasma triglyceride levels of 3,500-5,000 mg/dl. GPIHBP1 is expressed highly in heart, adipose tissue, and skeletal muscle, the same tissues that express high levels of lipoprotein lipase (LPL). In each of these tissues, GPIHBP1 is located in capillary endothelial cells. Chinese hamster ovary (CHO) cells transfected with a GPIHBP1 expression vector bind LPL and chylomicrons avidly. The expression of GPIHBP1 in mice is modulated by fasting and refeeding and is also regulated by peroxisome proliferator-activated receptor (PPAR)g agonists. Here, we review recent progress in understanding GPIHBP1 and discuss its role in lipolysis.-Beigneux, A. P., B. S. J. Davies, A. Bensadoun, L. G. Fong, and S. G. Young. GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins. J. Lipid Res. 2009. 50: S57-S62. Supplementary key words chylomicronsFor 50 years, the entire history of the Journal of Lipid Research, it has been known that plasma triglycerides can be cleared by a dedicated enzyme, lipoprotein lipase (LPL) (1). The lipolytic processing of triglyceride-rich lipoproteins occurs mainly in heart, skeletal muscle, and adipose tissue (2-4). We now know that LPL is synthesized by myocytes and adipocytes and then finds its way into capillaries, where lipolysis takes place (2, 3). In the absence of LPL (or its cofactor apolipoprotein CII), lipolytic processing of lipoproteins cannot occur, leading to severe hypertriglyceridemia ("chylomicronemia") (2).For the past few decades, the protagonists in lipolysis (i.e., LPL, apo-CII) have remained the same, and their functions have been studied thoroughly. Along the way, several "supporting actors" (e.g., apo-CIII, apo-AV, ANGPTL3, ANGPTL4) have appeared (5-8). These molecules regulate the efficiency of lipolysis, and deficiencies in these proteins perturb plasma triglyceride levels. Over the past few years, the functions of these molecules have been investigated by multiple laboratories.Recently, just as we were beginning to think that the broad outlines of lipolysis were understood, a new molecule, GPIHBP1, appeared on the scene (Fig. 1) (9-11). GPIHPB1 is required for lipolysis, and a deficiency of this protein causes frank chylomicronemia. Interestingly, GPIHBP1 is synthesized by endothelial cells (9). The discovery of an endothelial cell protein for lipolysis is welcome news, at least in our opinion. Prior to the discovery of GPIHBP1, dogma held that lipolysis, a process occurring within capillaries, actually took place without any truly dedicated endothelial cell protein. That, in our view, seemed odd. With the discovery of GPIHBP1, a void has been filled. No longer can endothelial cells be viewed as playing a passive role in lipolysis, merely "hosting" a lipolytic process controlled by surrounding tissues. Wi...

Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion

“…Direct evaluation of this hypothesis is complicated because Lpl Ϫ / Ϫ mice die shortly after birth. Sonnenburg et al ( 48 ) found that genetic ablation or antibody-mediated inactivation of ANGPTL3 decreased plasma TG levels by 26% in fed mice lacking GPIHBP1, a protein required for the transport of LPL to the capillary endothelial surface ( 49 ). Unfortunately, those authors did not report plasma levels of cholesterol for this experiment.…”

Effects of the Prosegment and pH on the Activity of PCSK9

“…The similarity of the N-terminal acidic sequence of PCSK9 to that of GPIHBP1, which enhances lipase hydrolysis of triglycerides in chylomicrons (31)(32)(33), led us to show that these domains could be swapped without a deleterious effect on the PCSK9 function (Fig. 6).…”

“…Thus, we noted a significant similarity in acidity and length of the Tyr 38 -sulfated, Ser 47 -phosphorylated aa 31-58, 31 QEDEDGDYEELV-LALRSEEDGLAEAPEH 58 , of PCSK9 to the heparin-like, Tyr-sulfated, acidic stretch, including aa 24 -51, 24 QEEEEED-EDHGPDDYDEEDEDEVEEEET 51 , at the N terminus of the glycosylphosphatidylinositol-anchored protein GPIHBP1. The latter domain binds lipoprotein lipase and apolipoprotein AV on chylomicrons, thereby enhancing lipoprotein lipase activity on triglycerides (31)(32)(33). Note that 13/14 acidic residues of PCSK9 (including the Tyr sulfation and Ser phosphorylation sites) align with similar residues in human GPIHBP1 (Fig.…”

Genetic determinants of plasma triglycerides

“…Gpihbp1 is expressed primarily in capillaries of heart, adipose tissue, and skeletal muscle, where it localizes to the luminal surface of endothelial cells ( 151,152 ). Gpihbp1 probably directs fat toward energy sinks, such as the heart and adipose tissue ( 153 ). Gpihbp1 is regulated by PPAR ␥ , with increased expression during fasting and return to baseline after refeeding ( 154 ).…”