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• W2014202221 abstract "At the endothelial cell surface, binding of chylomicrons and lipoprotein lipase (LpL), the major enzyme involved in the processing of these triglyceride-rich lipoproteins, is thought to involve electrostatic interactions with glycosaminoglycans. A new study published in this issue of Cell Metabolism (Beigneux et al., 2007Beigneux A. Davies B.S.J. Gin P. Weinstein M.M. Farber E. Qiao X. Peale F. Bunting S. Walzem R.L. Wong J.S. et al.Cell Metab. 2007; 5 (this issue): 279-291Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar) provides evidence for a specific chylomicron/LpL receptor, which may serve as a platform for LpL-mediated processing of chylomicrons on the capillary endothelium. At the endothelial cell surface, binding of chylomicrons and lipoprotein lipase (LpL), the major enzyme involved in the processing of these triglyceride-rich lipoproteins, is thought to involve electrostatic interactions with glycosaminoglycans. A new study published in this issue of Cell Metabolism (Beigneux et al., 2007Beigneux A. Davies B.S.J. Gin P. Weinstein M.M. Farber E. Qiao X. Peale F. Bunting S. Walzem R.L. Wong J.S. et al.Cell Metab. 2007; 5 (this issue): 279-291Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar) provides evidence for a specific chylomicron/LpL receptor, which may serve as a platform for LpL-mediated processing of chylomicrons on the capillary endothelium. Chylomicrons are triglyceride-rich lipoproteins that are synthesized by the intestinal epithelium and deliver dietary lipids to peripheral tissues. In the bloodstream, triglycerides transported by chylomicrons undergo lipolysis through the action of lipoprotein lipase (LpL) at the surface of the capillary endothelium, liberating free fatty acids for uptake by tissues. It is thought that LpL, which is synthesized by nonendothelial parenchymal cells, is tethered to the endothelial cell surface through electrostatic interactions between the positively charged heparin-binding domains of LpL and negatively charged glycosaminoglycans (GAGs), such as heparan sulfate proteoglycans (HSPGs) (Goldberg, 1996Goldberg I.J. J. Lipid Res. 1996; 37: 693-707Abstract Full Text PDF PubMed Google Scholar). Non-HSPG-binding proteins have been proposed to mediate association of LpL to the cell surface, similar to that observed for some apolipoproteins and growth factors. However, the molecular basis of the LpL-chylomicron interaction is poorly understood. In this issue, Beigneux et al., 2007Beigneux A. Davies B.S.J. Gin P. Weinstein M.M. Farber E. Qiao X. Peale F. Bunting S. Walzem R.L. Wong J.S. et al.Cell Metab. 2007; 5 (this issue): 279-291Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar report on the identification of an endothelium-expressed protein, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), which is required for the lipolytic processing of chylomicrons. GPIHBP1 was previously identified as a GPI-linked protein that facilitated the binding of high-density lipoproteins to cultured cells (Ioka et al., 2003Ioka R.X. Kang M.J. Kamiyama S. Kim D.H. Magoori K. Kamataki A. Ito Y. Takei Y.A. Sasaki M. Suzuki T. et al.J. Biol. Chem. 2003; 278: 7344-7349Crossref PubMed Scopus (75) Google Scholar). To examine the role of GPIHBP1 in lipoprotein metabolism, Beigneux and colleagues generated Gpihbp1−/− mice by gene targeting. Surprisingly, these mice developed milky plasma with markedly elevated plasma triglycerides, the vast majority of which were associated with the chylomicron/VLDL fraction. The authors demonstrate that GPIHBP1 is highly expressed in the same tissues that express LpL (i.e., heart and adipose tissue) and localizes to the luminal face of the capillary endothelium. Moreover, Beigneux and colleagues convincingly show that expression of GPIHBP1 confers upon cultured cells the ability to bind LpL and chylomicrons, prompting them to propose a role for GPIHBP1 as a molecular platform for LpL-mediated processing of chylomicrons on the capillary endothelium. How might GPIHBP1 mediate LpL and chylomicron binding? GPIHBP1 harbors a strongly acidic negatively charged domain that could potentially bind to the positively charged domains of apolipoproteins (e.g., apo-B48, apo-E, and apo-AV) contained in chylomicrons (Figure 1A). Likewise, the acidic domain may also serve as the binding site for LpL, which contains positively charged heparin-binding domains. A key question is how GPIHBP1 might facilitate interactions between LpL and chylomicrons. If GPIHBP1 binds only a single ligand (either a chylomicron particle or LpL), then there must be a mechanism to promote interaction between GPIHBP1-chylomicron and GPIHBP1-LpL hetero-oligomeric complexes (Figure 1B). Beigneux et al., 2007Beigneux A. Davies B.S.J. Gin P. Weinstein M.M. Farber E. Qiao X. Peale F. Bunting S. Walzem R.L. Wong J.S. et al.Cell Metab. 2007; 5 (this issue): 279-291Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar suggest that the GPI-anchored complexes might cluster in raft domains in the plasma membrane, thereby bringing LpL into contact with chylomicrons. Alternatively, GPIHBP1, which is a member of a class of GPI-anchored surface receptors known to exist as homodimers (Cunningham et al., 2003Cunningham O. Andolfo A. Santovito M.L. Iuzzolino L. Blasi F. Sidenius N. EMBO J. 2003; 22: 5994-6003Crossref PubMed Scopus (124) Google Scholar), may facilitate interaction through dimerization (Figure 1C). In either event, chylomicron-associated triglyceride would be accessible to LpL, leading to release of free fatty acids and transport across the endothelial surface, possibly through CD36- or FATP-dependent mechanisms (Schaffer, 2002Schaffer J.E. Am. J. Physiol. Endocrinol. Metab. 2002; 282: E239-E246PubMed Google Scholar). Delineation of the role of the GPIHBP1 acidic domain in chylomicron and/or LpL binding and the stoichiometry of the ligand-receptor interaction awaits future structure-function and binding studies. Further insight into these mechanisms may be revealed through the detection of GPIHBP1 homodimers and by mapping of amino acid residues required for homodimer formation. According to this model, efficient lipolytic processing of chylomicrons requires binding of lipoprotein particles to GPIHBP1, which serves as a platform for lipoprotein-LpL interaction. While the precise nature of the GPIHBP1-chylomicron interaction is not yet known, the demonstration by Beigneux et al., 2007Beigneux A. Davies B.S.J. Gin P. Weinstein M.M. Farber E. Qiao X. Peale F. Bunting S. Walzem R.L. Wong J.S. et al.Cell Metab. 2007; 5 (this issue): 279-291Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar that GPIHBP1 expression increases apo-AV binding suggests that this chylomicron-associated, exchangeable apolipoprotein might serve as a ligand for GPIHBP1. Indeed, apo-AV deficiency is characterized by impaired LpL hydrolysis and elevated serum triglycerides (Grosskopf et al., 2005Grosskopf I. Baroukh N. Lee S.J. Kamari Y. Harats D. Rubin E.M. Pennacchio L.A. Cooper A.D. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2573-2579Crossref PubMed Scopus (111) Google Scholar), although not to the extreme level that occurs in Gpihbp1−/− mice. This implies that apolipoproteins other than apo-AV may mediate chylomicron binding. An intriguing possibility raised by the authors is that GPIHBP1 may serve as a receptor for apo-B48, the key structural apolipoprotein in chylomicrons. The observation that apo-B48 and chylomicrons are uniquely found in mammals and that GPIHBP1 is present only in mammalian genomes lends plausibility to this hypothesis. The processing of apo-B100-containing lipoproteins (e.g., VLDL) could occur through interaction of endothelium-expressed HSPGs with apo-B100 heparin-binding domains, high-affinity sites that are absent in apo-B48 (Weisgraber and Rall, 1987Weisgraber K.H. Rall Jr., S.C. J. Biol. Chem. 1987; 262: 11097-11103Abstract Full Text PDF PubMed Google Scholar). Apo-B48-containing chylomicrons, in contrast to apo-B100-containing lipoproteins, may depend to a greater extent on GPIHBP1 for LpL-mediated lipolysis. An apo-B48 receptor, therefore, might provide an important physiological advantage by promoting preferential processing of chylomicron-delivered dietary triglycerides in GPIHBP1-expressing tissues (e.g., heart and adipose tissue). In theory, this could not only safeguard the supply of free fatty acids for cardiac energetics and adipose tissue storage but also channel to the heart dietary essential fatty acids, such as n-3 polyunsaturated fatty acids, which are known to have antiatherogenic and antiarrhythmic properties (Kang and Leaf, 1996Kang J.X. Leaf A. Circulation. 1996; 94: 1774-1780Crossref PubMed Scopus (210) Google Scholar). Several inherited disorders causing accumulation of chylomicrons in plasma have been described in humans. These chylomicronemia syndromes are caused exclusively by deficiency of either LpL or apoC-II, an essential cofactor for LpL (Brunzell and Deeb, 2001Brunzell J.D. Deeb S.S. Familial lipoprotein lipase deficiency, apo CII deficiency, and hepatic lipase deficiency.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. Volume 2. McGraw-Hill, New York2001: 2789-2816Google Scholar). So far, no cases of chylomicronemia associated with defective binding of chylomicrons or LpL to endothelial cells have been described. It is possible that homozygous GPIHBP1 deficiency in humans, unlike in mice, causes embryonic lethality. Alternatively, other receptors might compensate for loss of GPIHBP1 function. While additional studies are needed to further define the molecular events involved in chylomicron processing, the identification of GPIHBP1 as a putative chylomicron/LpL receptor is an important milestone in our understanding of lipoprotein physiology and offers new insight into this complex and carefully choreographed metabolic pathway for the delivery of lipid nutrients to cells. Glycosylphosphatidylinositol-Anchored High-Density Lipoprotein-Binding Protein 1 Plays a Critical Role in the Lipolytic Processing of ChylomicronsBeigneux et al.Cell MetabolismApril 04, 2007In BriefThe triglycerides in chylomicrons are hydrolyzed by lipoprotein lipase (LpL) along the luminal surface of the capillaries. However, the endothelial cell molecule that facilitates chylomicron processing by LpL has not yet been defined. Here, we show that glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a critical role in the lipolytic processing of chylomicrons. Gpihbp1-deficient mice exhibit a striking accumulation of chylomicrons in the plasma, even on a low-fat diet, resulting in milky plasma and plasma triglyceride levels as high as 5000 mg/dl. Full-Text PDF Open Archive" @default.
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• W2014202221 title "Chylomicrons and Lipoprotein Lipase at the Endothelial Surface: Bound and GAG-ged?" @default.
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