Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells

Abstract

The lipolytic processing of triglyceride-rich lipoproteins (e.g., chylomicrons, very low density lipoproteins) by lipoprotein lipase (LPL) is the central event in plasma triglyceride metabolism and plays a crucial role in the delivery of lipid nutrients to parenchymal cells (e.g., adipocytes, myocytes) ( 1-4 ). LPL is synthesized by parenchymal cells and secreted into the interstitial spaces, but it needs to reach the capillary lumen in order to hydrolyze the triglycerides in plasma lipoproteins. Recent studies showed that GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, binds LPL avidly ( 5 ) and is required for the transport of LPL to the capillary lumen ( 6 ). In the absence of GPIHBP1, LPL accumulates in the interstitial spaces around parenchymal cells and is unable to process triglyceride-rich lipoproteins in the bloodstream, resulting in markedly elevated plasma triglyceride levels and interfering with the delivery of lipid nutrients to parenchymal cells ( 5-7 ).Although GPIHBP1 is essential for the delivery of LPL to the luminal face of capillaries, the cellular mechanisms for moving GPIHBP1 and LPL across endothelial cells are poorly defi ned. It is unclear whether GPIHBP1 and LPL move unidirectionally from the basolateral face of endothelial cells to LPL's site of action along the capillary lumen or whether "backwards traffi cking" also occurs (i.e., movement of GPIHBP1 and LPL from the lumen to the basolateral face of cells). A second issue is whether GPIHBP1 Abstract Lipoprotein lipase (LPL) is secreted into the interstitial spaces by adipocytes and myocytes but then must be transported to the capillary lumen by GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells. The mechanism by which GPIHBP1 and LPL move across endothelial cells remains unclear. We asked whether the transport of GPIHBP1 and LPL across endothelial cells was uni-or bidirectional. We also asked whether GPIHBP1

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

“…These findings may have considerable in vivo significance in light of recent data showing that, in humans, serum ANGPTL4 levels do not correlate with plasma triglyceride levels and that LPL travels bidirectionally across endothelial cells (24,25). These data have led to the suggestion that ANGPTL4 could inhibit LPL in the subendothelial space rather than on the endothelial surface (25). Here, we report our data showing a noncompetitive mechanism for ANGPTL4 inhibition of LPL and discuss its possible physiological implications.…”

“…The protein GPIHBP1 binds to the endothelium of capillary cells where it provides a platform for LPL to process triglycerides from lipoproteins (41). GPIHBP1 also helps transport LPL across the endothelial cells, and a recent study has shown that this transport is bidirectional (25,42). ANGPTL4 could thus inhibit LPL in either the subendothelial space or on the surface of the capillary endothelium, and a number of recent studies support the former option.…”

“…Inhibited LPL was found in a complex with ANGPTL4, and superstoichiometric ratios of ANGPTL4/LPL were required for complete inhibition. These findings may have considerable in vivo significance in light of recent data showing that, in humans, serum ANGPTL4 levels do not correlate with plasma triglyceride levels and that LPL travels bidirectionally across endothelial cells (24,25). These data have led to the suggestion that ANGPTL4 could inhibit LPL in the subendothelial space rather than on the endothelial surface (25).…”

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

“…Our studies shed some light on what the possible efficacy of ANGPTL4 might be in different physiological contexts. It has been previously suggested that the most prevalent site of ANGPTL4-mediated LPL inactivation may be in the interstitial space (11,39). Concentrations of ANGPTL4 in the interstitial space of various tissues are not known, but they are likely to be high in tissues such as adipose where gene expression is high (20).…”

Recent advances in physiological lipoprotein metabolism

“…GPIHBP1 provides an important platform for LPL-mediated hydrolysis of chylomicron triglycerides. Davies et al [78] showed that GPIHBP1 was effective in transporting LPL from the basolateral to the apical surface of endothelial cells. Recently, it has been suggested that LPL and GPIHBP1 move bidirectionally across the cell surface, however, the understanding of the molecular processes of the transport remains incomplete [79].…”