doi: 10.1161/ATVBAHA.109.187823
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2009 American Heart Association, Inc.
Editorial |
Some Things Just Have to Be Done In Vivo
GPIHBP1, Caloric Delivery, and the Generation of Remnant Lipoproteins
From the Section of Endocrinology, Diabetes, and Metabolism, Temple University School of Medicine, Philadelphia, Pa.
Correspondence to Kevin Jon Williams, MD, Section of Endocrinology, Diabetes and Metabolism, Temple University School of Medicine, 3322 North Broad Street, Medical Office Building, Room 212, Philadelphia, PA 19140. E-mail K_Williams{at}mail.jci.tju.edu
 |
Abstract |
|---|
 Top Abstract References |
|---|
The recent discovery of a dysfunctional mutation of GPIHBP1 in a man with chylomicronemia implicates this protein in human physiology. GPIHBP1 can be placed in the larger context of other molecular participants in chylomicron docking and hydrolysis on microvascular endothelium, caloric delivery, and remnant lipoprotein generation. Critical questions include the regulation—and dysregulation—of these processes in states of overnutrition, underexertion, obesity, insulin resistance, and diabetes.
For decades, we were convinced that heparan sulfate proteoglycans (HSPGs) on the microvascular endothelium of adipose tissue and striated muscle served as the docking site for chylomicrons (CMs) during their lipolysis by lipoprotein lipase (LpL).1 A serendipitous observation of milky plasma in GPIHBP1-deficient mice and its skillful elucidation by the Young laboratory implicate this molecule instead.2,3 The work represents a major revision in our understanding of lipoprotein-mediated caloric delivery. In the current issue of ATVB, Beigneux et al report a novel dysfunctional missense mutation in GPIHBP1 that they found in a chylomicronemic man, thereby extending the relevance of their findings to humans.4
See accompanying article on page 956
The physiological role of GPIHBP1 was not found by cloning the protein, which was originally identified as an HDL-binding molecule, hence its name.5 Nor was its role revealed by sequencing the human genome, nor by any genome-wide association studies.6 Cell culture also failed,7–10 because endothelial cells promptly lose expression of GPIHBP1 in vitro.11
The Figure presents a recent attempt to place GPIHBP1 in the larger context of other molecular participants in CM docking, hydrolysis, caloric delivery, and remnant lipoprotein generation.12 Some of these molecules, such as caveolin-113,14 and CD36,15,16 have been implicated in mice and humans in vivo. But some processes, such as HSPG-mediated endocytosis and destruction of LpL by adipocytes17,18 and transendothelial transport of LpL by HSPGs and the VLDL receptor,19 have been documented only in vitro.
|
Nevertheless, the available evidence suggests that key molecular participants share crucial features of location and regulation. Regarding location, hydrolysis of CM triglyceride and then tissue uptake of nonesterified fatty acids (NEFAs) may be facilitated by being concentrated within cholesterol-rich membrane microdomains, also known as rafts.12 The major HSPGs of endothelial cells include the transmembrane syndecans and the GPI-anchored glypicans. Syndecan HSPGs move laterally into rafts on clustering,20,21 and binding a dimer of LpL, the enzymatically active form, appears to be a sufficient trigger.20 GPI-anchored molecules also move into rafts on clustering.22 Thus, syndecans, glypicans, and GPIHBP1 should come into close proximity within rafts after the transendothelial transport of dimeric LpL, thereby facilitating the transfer of this enzyme from HSPGs onto higher-affinity binding sites on GPIHBP1. Likewise, the CD36 fatty acid translocase also localizes to rafts,23 which could facilitate its ability to accept NEFAs from LpL-GPIHBP1-CM complexes during triglyceride hydrolysis (Figure). Consistent with this model, knock-out of caveolin-1, a scaffolding molecule required for the formation of certain types of cholesterol-rich microdomains, impairs lipolysis of postprandial lipoproteins and the importation of NEFAs into adipose tissue.13 Similar effects have been associated with a nonsense mutation of human caveolin-1.14
To complete this picture, we need to address several additional questions. What molecules mediate transendothelial transport of LpL in vivo? Endothelium does not make LpL, but must acquire it from underlying adipocytes and myocytes. As noted above, cell-culture data implicate HSPGs and the VLDL receptor. The VLDL receptor was reported to affect LpL regulation in vivo, possibly related to transendothelial transport.24 If HSPGs are involved in vivo, which ones? Syndecans-1, -2, and -4 and glypican-1 would be attractive candidates, owing to their expression by cultured endothelial cells25,26 and their ability to directly mediate ligand internalization.20,21,27–29 Syndecans bind LpL in vitro20,27 and mediate endocytosis via rafts.20,30 Glypican-1 undergoes caveolar-associated recycling,28 and digestion of cultured adipocytes and myocytes with phosphatidylinositol-specific phospholipase-C releases HSPG-bound LpL,31–33 although digestion of cultured endothelial cells did not.10 Thus, under some circumstances, syndecans and glypicans function as LpL receptors in vitro, but their role in LpL trafficking across the endothelium in vivo remains unknown.
Could GPIHBP1 be involved in transendothelial transport of LpL? It seems unlikely, given its apparently exclusive expression on the luminal surface.2 But why, then, is the amount of LpL released into postheparin plasma affected by a deficiency of functional GPIHBP1, even though tissue stores of the enzyme remain normal?34 Plasma levels of LpL were low at early, but not later, time points after a heparin injection into GPIHBP1-deficient mice,34 and LpL was low in a single sample of postheparin plasma from the individual with the dysfunctional missense mutation.4 In addition, GPIHBP1 deficiency blocked the release of LpL into plasma at all time points tested after an injection of artificial triglyceride emulsion particles.34
There may be two pools of LpL, one displayed on luminal GPIHBP1 and one deep within adipose tissue and striated muscle.34 Both pools might be eventually accessible to heparin, which has been reported to readily pass through arterial endothelium,35 but only the pool adherent to GPIHBP1 would be accessible to emulsions and able to hydrolyze lipoprotein triglyceride. On the other hand, because heparin inhibits transendothelial transport of LpL in vitro,19 heparin that reaches the tissue pool of LpL might strand it there, rather than facilitating its release into plasma. Moreover, delayed release of nonluminal depots of LpL has been documented from hearts perfused with heparin, but the mechanism implicated in that study was the gradual transport of this enzyme to the endothelial surface, after which it was nearly immediately released by heparin in the perfusate.36
Alternatively, if transfer of LpL from endothelial HSPGs and VLDL receptors onto GPIHBP1 does in fact occur, it could prevent HSPG- or VLDL receptor-mediated endocytosis or transcytosis back into the subendothelial space, particularly if those molecules continuously recycle. Evidence in vivo indirectly supports the existence of a pool of LpL molecules that recirculate between the luminal surface of the endothelium and extravascular sites in adipose tissue.37 Cultured endothelial cells also internalize LpL and then recycle it back to the cell surface intact.17,33,38 Here, the model presumes that LpL cycling back and forth across the luminal endothelial membrane remains inaccessible to triglyceride-rich lipoproteins and emulsion particles in the bloodstream, unless the enzyme can move onto GPIHBP1. As a speculative example, LpL bound to the heparan sulfate side-chains of glypican would sit close to the plasma membrane (Figure), where very large particles might not be able to approach.39
Does GPIHBP1 affect the enzymatic activity of LpL? It has long been know that heparin-induced release of LpL from its binding sites on the luminal surface of endothelium quickly accelerates the hydrolysis of triglyceride-rich lipoproteins in plasma in vivo.1,34,40,41 It could simply be a matter of better access to substrate when the enzyme is in solution than when it is confined to a surface, but it is also possible that the conformation of LpL is altered by its association with GPIHBP1. If the latter, the conformational changes could be regulated.
What physical determinants allow remnant lipoproteins and artificial emulsions to acquire LpL from the luminal surface of the endothelium? In normal physiology, the shift in apoprotein composition before CM docking (apoB48, apoA-V, apoC-II, apoE) versus after remnant release (apoB48, LpL, apoE) sets the stage for rapid hepatic uptake via the unusual, highly charged HSPGs that are displayed on the basal surface of healthy hepatocytes12,27,42–44 (Figure). Postprandial apoB48-containing lipoproteins that contain LpL are cleared from human plasma much faster than particles without this important molecule,45 consistent with the earlier suggestion that LpL should be regarded as an apoprotein whose function is recognition by hepatic HSPGs.27,42 Do changes in particle size and composition during lipolysis enhance adsorption of LpL? A role for apoB48 seems unlikely, because artificial triglyceride emulsions acquire LpL in vivo in wild-type animals,46 consistent with well-established physical properties of the enzyme.1,47 Do GPIHBP1 or other proteins alter their conformations to facilitate LpL release to remnants or emulsions during lipolysis? Generation of NEFAs in excess of tissue importation appears to be a physiological stimulus for the release of LpL from endothelium in vivo, thereby slowing local lipolysis.48 Thus, NEFAs may be one factor to dissociate LpL-GPIHBP1 complexes.
But the most interesting questions relate to human physiology and pathophysiology. Fasting, high-fat feeding, and PPAR
activation increase Gpihbp1 mRNA levels in white adipose tissue, brown adipose tissue, and striated muscle of mice, consistent with a role in directing caloric delivery.11 If differential regulation of the GPIHBP1 protein among these tissues is found, then it would join an important list of molecules that control the metabolic branch point between delivery of CM triglycerides into white adipose tissue for storage, versus uptake into brown adipose tissue and striated muscle for combustion.12,49 The regulation—or dysregulation—of these molecules in states of overnutrition, underexertion, obesity, insulin resistance, diabetes, and related conditions is becoming an increasingly significant medical issue.
|
Acknowledgments |
|---|
Disclosures
None.
|
References |
|---|
|
TopAbstractReferences |
|---|
1. Olivecrona T, Bengtsson-Olivecrona G. Lipoprotein lipase from milk-the model enzyme in lipoprotein lipase research. In: Borensztajn J, ed. Lipoprotein Lipase. Evener: Chicago, Ill; 1987: 15–58.
2. Beigneux AP, Davies BS, Gin P, Weinstein MM, Farber E, Qiao X, Peale F, Bunting S, Walzem RL, Wong JS, Blaner WS, Ding ZM, Melford K, Wongsiriroj N, Shu X, de Sauvage F, Ryan RO, Fong LG, Bensadoun A, Young SG. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 2007; 5: 279–291.[CrossRef][Medline] [Order article via Infotrieve]
3. Young SG, Davies BS, Fong LG, Gin P, Weinstein MM, Bensadoun A, Beigneux AP. GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons. Curr Opin Lipidol. 2007; 18: 389–396.[CrossRef][Medline] [Order article via Infotrieve]
4. Beigneux AP, Franssen R, Bensadoun A, Gin P, Melford K, Peter J, Walzem RL, Weinstein MM, Davies BSJ, Kuivenhoven JA, Kastelein JJP, Fong LG, Dallinga-Thie GM, Young SG. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler Thromb Vasc Biol. 2009; 29: 956–962.
5. Ioka RX, Kang MJ, Kamiyama S, Kim DH, Magoori K, Kamataki A, Ito Y, Takei YA, Sasaki M, Suzuki T, Sasano H, Takahashi S, Sakai J, Fujino T, Yamamoto TT. Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein, GPI-HBP1. J Biol Chem. 2003; 278: 7344–7349.
6. Lusis AJ, Pajukanta P. A treasure trove for lipoprotein biology. Nat Genet. 2008; 40: 129–130.[CrossRef][Medline] [Order article via Infotrieve]
7. Shimada K, Gill PJ, Silbert JE, Douglas WHJ, Fanburg BL. Involvement of cell surface heparan sulfate in the binding of lipoprotein lipase to cultured bovine endothelial cells. J Clin Invest. 1981; 68: 995–1002.[Medline] [Order article via Infotrieve]
8. Cheng C-F, Oosta GM, Bensadoun A, Rosenberg RD. Binding of lipoprotein lipase to endothelial cells in culture. J Biol Chem. 1981; 256: 12893–12898.
9. Wang-Iverson P, Brown WV. Interaction of lipoprotein lipase with cultured endothelial cells. Ann NY Acad Sci. 1982; 401: 92–101.[CrossRef][Medline] [Order article via Infotrieve]
10. Saxena U, Klein MG, Goldberg IJ. Identification and characterization of the endothelial cell surface lipoprotein lipase receptor. J Biol Chem. 1991; 266: 17516–17521.
11. Davies BS, Waki H, Beigneux AP, Farber E, Weinstein MM, Wilpitz DC, Tai LJ, Evans RM, Fong LG, Tontonoz P, Young SG. The expression of GHIBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by peroxisome proliferator-activated receptor-gamma. Mol Endocrinol. 2008; 22: 2496–2504.
12. Williams KJ. Molecular processes that handle - and mishandle - dietary lipids. J Clin Invest. 2008; 118: 3247–3259.[CrossRef][Medline] [Order article via Infotrieve]
13. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem. 2002; 277: 8635–8647.
14. Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR, Semple RK, O'Rahilly S, Dugail I, Capeau J, Lathrop M, Magre J. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008; 93: 1129–1134.
15. Coburn CT, Knapp FF Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000; 275: 32523–32529.
16. Yanai H, Watanabe I, Ishii K, Morimoto M, Fujiwara H, Yoshida S, Hui SP, Matsuno K, Chiba H. Attenuated aerobic exercise capacity in CD36 deficiency. J Med Genet. 2007; 44: 445–447.
17. Friedman G, Chajek-Shaul T, Olivecrona T, Stein O, Stein Y. Fate of milk 125I-labeled lipoprotein lipase in cells in culture. Comparison of lipoprotein lipase- and non-lipoprotein lipase-synthesizing cells. Biochim Biophys Acta. 1982; 711: 114–122.[Medline] [Order article via Infotrieve]
18. Cisar LA, Hoogewerf AJ, Cupp M, Rapport CA, Bensadoun A. Secretion and degradation of lipoprotein lipase in cultured adipocytes. Binding of lipoprotein lipase to membrane heparan sulfate proteoglycans is necessary for degradation. J Biol Chem. 1989; 264: 1767–1774.
19. Obunike JC, Lutz EP, Li Z, Paka L, Katopodis T, Strickland DK, Kozarsky KF, Pillarisetti S, Goldberg IJ. Transcytosis of lipoprotein lipase across cultured endothelial cells requires both heparan sulfate proteoglycans and the very low density lipoprotein receptor. J Biol Chem. 2001; 276: 8934–8941.
20. Fuki IV, Meyer ME, Williams KJ. Transmembrane and cytoplasmic domains of syndecan mediate a multi-step endocytic pathway involving detergent-insoluble membrane rafts. Biochem J. 2000; 351: 607–612.[CrossRef][Medline] [Order article via Infotrieve]
21. Tkachenko E, Lutgens E, Stan RV, Simons M. Fibroblast growth factor 2 endocytosis in endothelial cells proceed via syndecan-4-dependent activation of Rac1 and a Cdc42-dependent macropinocytic pathway. J Cell Sci. 2004; 117: 3189–3199.
22. Mayor S, Rothberg KG, Maxfield FR. Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking. Science. 1994; 264: 1948–1951.
23. Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W. FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. Mol Biol Cell. 2005; 16: 24–31.
24. Yagyu H, Lutz EP, Kako Y, Marks S, Hu Y, Choi SY, Bensadoun A, Goldberg IJ. Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency. J Biol Chem. 2002; 277: 10037–10043.
25. Kojima T, Shworak NW, Rosenberg RD. Molecular cloning and expression of two distinct cDNA-encoding heparan sulfate proteoglycan core proteins from a rat endothelial cell line. J Biol Chem. 1992; 267: 4870–4877.
26. Renne T, Dedio J, David G, Muller-Esterl W. High molecular weight kininogen utilizes heparan sulfate proteoglycans for accumulation on endothelial cells. J Biol Chem. 2000; 275: 33688–33696.
27. Fuki IV, Kuhn KM, Lomazov IR, Rothman VL, Tuszynski GP, Iozzo RV, Swenson TL, Fisher EA, Williams KJ. The syndecan family of proteoglycans: novel receptors mediating internalization of atherogenic lipoproteins in vitro. J Clin Invest. 1997; 100: 1611–1622.[Medline] [Order article via Infotrieve]
28. Belting M, Mani K, Jonsson M, Cheng F, Sandgren S, Jonsson S, Ding K, Delcros JG, Fransson LA. Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J Biol Chem. 2003; 278: 47181–47189.
29. Boyanovsky BB, Shridas P, Simons M, van der Westhuyzen DR, Webb NR. Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified low density lipoprotein. J Lipid Res. 2009; 50: 641–650.
30. Chen K, Liu M-L, Williams KJ. Molecular determinants of endocytosis and tyrosine phosphorylation within the cytoplasmic tail of human syndecan-1, a receptor for remnant lipoproteins. Circulation. 2008; 118 (suppl. 2): S453. Abstract.
31. Chajek-Shaul T, Halimi O, Ben-Naim M, Stein O, Stein Y. Phosphatidylinositol-specific phospholipase C releases lipoprotein lipase from the heparin releasable pool in rat heart cell cultures. Biochim Biophys Acta. 1989; 1014: 178–183.[Medline] [Order article via Infotrieve]
32. Braun JE, Severson DL. Diabetes reduces heparin- and phospholipase C-releasable lipoprotein lipase from cardiomyocytes. Am J Physiol. 1991; 260: E477–E485.[Medline] [Order article via Infotrieve]
33. Misra KB, Kim KC, Cho S, Low MG, Bensadoun A. Purification and characterization of adipocyte heparan sulfate proteoglycans with affinity for lipoprotein lipase. J Biol Chem. 1994; 269: 23838–23844.
34. Weinstein MM, Beigneux AP, Davies BS, Gin P, Yin L, Estrada K, Melford K, Bishop JR, Esko JD, Fong LG, Bensadoun A, Young SG. Abnormal patterns of lipoprotein lipase release into the plasma in GPIHBP1-deficient mice. J Biol Chem. 2008; 283: 34511–34518.
35. Lovich MA, Philbrook M, Sawyer S, Weselcouch E, Edelman ER. Arterial heparin deposition: role of diffusion, convection, and extravascular space. Am J Physiol. 1998; 275: H2236–H2242.[Medline] [Order article via Infotrieve]
36. Qi D, Kuo KH, Abrahani A, An D, Qi Y, Heung J, Kewalramani G, Pulinilkunnil T, Ghosh S, Innis SM, Rodrigues B. Acute intralipid infusion reduces cardiac luminal lipoprotein lipase but recruits additional enzyme from cardiomyocytes. Cardiovasc Res. 2006; 72: 124–133.
37. Wu G, Olivecrona G, Olivecrona T. The distribution of lipoprotein lipase in rat adipose tissue. Changes with nutritional state engage the extracellular enzyme. J Biol Chem. 2003; 278: 11925–11930.
38. Saxena U, Klein MG, Goldberg IJ. Metabolism of endothelial cell-bound lipoprotein lipase. Evidence for heparan sulfate proteoglycan-mediated internalization and recycling. J Biol Chem. 1990; 265: 12880–12886.
39. Williams KJ, Fuki IV. Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism. Curr Opin Lipidol. 1997; 8: 253–262.[Medline] [Order article via Infotrieve]
40. Hahn PF. Abolishment of alimentary lipemia following injection of heparin. Science. 1943; 98: 19–20.
41. Anfinsen CB, Boyle E, Brown RK. The role of heparin in lipoprotein metabolism. Science. 1952; 115: 583–586.
42. Williams KJ, Fless GM, Petrie KA, Snyder ML, Brocia RW, Swenson TL. Mechanisms by which lipoprotein lipase alters cellular metabolism of lipoprotein(a), low density lipoprotein, and nascent lipoproteins. Roles for low density lipoprotein receptors and heparan sulfate proteoglycans. J Biol Chem. 1992; 267: 13284–13292.
43. Williams KJ, Liu M-L, Zhu Y, Xu X, Davidson WR, McCue P, Sharma K. Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II. Diabetes. 2005; 54: 1116–1122.
44. MacArthur JM, Bishop JR, Stanford KI, Wang L, Bensadoun A, Witztum JL, Esko JD. Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J Clin Invest. 2007; 117: 153–164.[CrossRef][Medline] [Order article via Infotrieve]
45. Zheng C, Murdoch SJ, Brunzell JD, Sacks FM. Lipoprotein lipase bound to apolipoprotein B lipoproteins accelerates clearance of postprandial lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006; 26: 891–896.
46. Hultin M, Bengtsson-Olivecrona G, Olivecrona T. Release of lipoprotein lipase to plasma by triacylglycerol emulsions. Comparison to the effect of heparin. Biochim Biophys Acta. 1992; 1125: 97–103.[Medline] [Order article via Infotrieve]
47. Borén J, Lookene A, Makoveichuk E, Xiang S, Gustafsson M, Liu H, Talmud P, Olivecrona G. Binding of low density lipoproteins to lipoprotein lipase is dependent on lipids but not on apolipoprotein B. J Biol Chem. 2001; 276: 26916–26922.
48. Peterson J, Bihain BE, Bengtsson-Olivecrona G, Deckelbaum RJ, Carpentier YA, Olivecrona T. Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport. Proc Natl Acad Sci USA. 1990; 87: 909–913.
49. Celi FS. Brown adipose tissue-when it pays to be inefficient. N Engl J Med. 2009; 360: 1553–1556.
Related Article:
Arterioscler Thromb Vasc Biol 2009 29: 956-962.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||