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• W2150436995 abstract "The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the remnants within the space of Disse, where apolipoprotein E secreted by hepatocytes enhances remnant binding and uptake. Heparan sulfate proteoglycans (HSPG), which are also abundant in the space of Disse, mediate this enhanced binding. Next, the remnants undergo further processing in the space of Disse by hepatic and lipoprotein lipases, which may also serve as ligands mediating remnant uptake. The final step, endocytosis by hepatocytes, appears to be mediated, at least in part, by the low density lipoprotein (LDL) receptor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the HSPG-LRP pathway. In addition, HSPG appear to function alone as a receptor and display unique handling properties for specific isoforms of apolipoprotein E.—Mahley, R. W., and Z-S. Ji. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J. Lipid Res. 1999. 40: 1–16. The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the remnants within the space of Disse, where apolipoprotein E secreted by hepatocytes enhances remnant binding and uptake. Heparan sulfate proteoglycans (HSPG), which are also abundant in the space of Disse, mediate this enhanced binding. Next, the remnants undergo further processing in the space of Disse by hepatic and lipoprotein lipases, which may also serve as ligands mediating remnant uptake. The final step, endocytosis by hepatocytes, appears to be mediated, at least in part, by the low density lipoprotein (LDL) receptor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the HSPG-LRP pathway. In addition, HSPG appear to function alone as a receptor and display unique handling properties for specific isoforms of apolipoprotein E. —Mahley, R. W., and Z-S. Ji. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J. Lipid Res. 1999. 40: 1–16. Remnant lipoproteins are cholesterol-enriched particles derived from the lipolytic processing of intestinal chylomicrons and hepatic very low density lipoproteins (VLDL). Chylomicrons (d < 0.95 g/ml) are synthesized by the small intestine to transport dietary triglyceride and cholesterol from the site of absorption by the intestinal epithelium to various cells of the body. In the circulation, the triglycerides in these particles are hydrolyzed by lipoprotein lipase (LPL), an enzyme found on the endothelial surfaces of capillaries, especially in adipose tissue, the heart, and skeletal muscle, resulting in the formation of chylomicron remnants. Relatively enriched in cholesterol by the loss of triglyceride, these remnants are normally cleared rapidly and efficiently from the plasma by the liver, through a process mediated primarily by apolipoprotein (apo) E. However, in animals whose diets are high in fat and cholesterol and in patients with type III hyperlipoproteinemia, chylomicron remnants accumulate in the plasma and have been linked to the development of accelerated atherosclerosis (for review, see refs. 1Mahley R.W. Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology.Circulation. 1985; 72: 943-948Google Scholar, 2Mahley R.W. Weisgraber K.H. Innerarity T.L. Rall Jr., S.C. Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism.J. Am. Med. Assoc. 1991; 265: 78-83Google Scholar, 3Mahley R.W. Weisgraber K.H. Farese Jr., R.V. Disorders of lipid metabolism.in: Wilson J.D. Foster D.W. Kronenberg H.M. Larsen P.R. Williams Textbook of Endocrinology. 9th edition. W.B. Saunders, Philadelphia1998: 1099-1153Google Scholar). Very low density lipoproteins (d < 1.006 g/ml) are synthesized in the liver and, like chylomicrons, fulfill a lipid transport function. The triglycerides in these particles are hydrolyzed by LPL in the plasma and in the liver, generating small, cholesterol-enriched lipoproteins known as intermediate density lipoproteins (IDL; d 1.006–1.019 g/ml) and low density lipoproteins (LDL; d 1.019–1.063 g/ml) (Fig. 1). Smaller VLDL and IDL are referred to as VLDL remnants and are atherogenic lipoproteins (1Mahley R.W. Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology.Circulation. 1985; 72: 943-948Google Scholar, 2Mahley R.W. Weisgraber K.H. Innerarity T.L. Rall Jr., S.C. Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism.J. Am. Med. Assoc. 1991; 265: 78-83Google Scholar, 3Mahley R.W. Weisgraber K.H. Farese Jr., R.V. Disorders of lipid metabolism.in: Wilson J.D. Foster D.W. Kronenberg H.M. Larsen P.R. Williams Textbook of Endocrinology. 9th edition. W.B. Saunders, Philadelphia1998: 1099-1153Google Scholar). VLDL remnants and chylomicron remnants are collectively called β-VLDL. About half of the VLDL remnants are cleared directly by the liver through an apoE-mediated process. The remainder are converted to LDL containing only apoB-100, the end product of VLDL catabolism and the major cholesterol-transporting lipoprotein in the plasma. By the early 1980s, Goldstein and Brown's classic studies of the LDL receptor pathway had shown that LDL bound via apoB-100 and were internalized and degraded primarily by the liver (4Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Google Scholar). Remnant lipoproteins also bound to the LDL receptor via apoE, the other ligand for the LDL receptor (Fig. 1) (5Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Google Scholar). However, it became obvious that remnant metabolism differed from LDL metabolism. Inpatients with familial hypercholesterolemia, LDL were not cleared normally and accumulated in the plasma as a result of defective or absent LDL receptors. Nevertheless, remnants were cleared rather normally. Therefore, an alternate pathway appeared to be involved. Hui and colleagues (6Hui D.Y. Innerarity T.L. Mahley R.W. Lipoprotein binding to canine hepatic membranes. Metabolically distinct apoE and apoB,E receptors.J. Biol. Chem. 1981; 256: 5646-5655Google Scholar, 7Hui D.Y. Innerarity T.L. Milne R.W. Marcel Y.L. Mahley R.W. Binding of chylomicron remnants and β-very low density lipoproteins to hepatic and extrahepatic lipoprotein receptors. A process independent of apolipoprotein B48.J. Biol. Chem. 1984; 259: 15060-15068Google Scholar) were among the first to undertake studies to define this alternate pathway and to highlight the role for a putative apoE receptor, independent of the LDL receptor. For many years, this pathway remained elusive. In 1988, Herz et al. (8Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor.EMBO J. 1988; 7: 4119-4127Google Scholar) identified a candidate molecule, the LDL receptor-related protein (LRP), which recognized only apoE and not apoB-100. Subsequently, the LRP was shown to be identical to the α2-macroglobulin receptor (9Kristensen T. Moestrup S.K. Gliemann J. Bendtsen L. Sand O. Sottrup-Jensen L. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the α2-macroglobulin receptor.FEBS Lett. 1990; 276: 151-155Google Scholar, 10Strickland D.K. Ashcom J.D. Williams S. Burgess W.H. Migliorini M. Argraves W.S. Sequence identity between the α2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor.J. Biol. Chem. 1990; 265: 17401-17404Google Scholar) and was demonstrated to be a multifunctional receptor capable of mediating the binding and uptake of several ligands (for review, see refs. 11Herz J. The LDL-receptor-related protein—portrait of a multifunctional receptor.Curr. Opin. Lipidol. 1993; 4: 107-113Google Scholar, 12Krieger M. Herz J. Structures and functions of multi-ligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar). In addition to the LRP, several other members of the LDL receptor family have been identified (for review, see refs. 12Krieger M. Herz J. Structures and functions of multi-ligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar, 13Herz J. Willnow T.E. Lipoprotein and receptor interactions in vivo.Curr. Opin. Lipidol. 1995; 6: 97-103Google Scholar, 14Schneider W.J. Nimpf J. Bujo H. Novel members of the low density lipoprotein receptor superfamily and their potential roles in lipid metabolism.Curr. Opin. Lipidol. 1997; 8: 315-319Google Scholar), and although these receptors can bind apoE-containing lipoproteins in vitro, they have not been shown to be expressed in the liver or to be involved in remnant lipoprotein catabolism. Other receptors, such as the asialoglycoprotein receptor (15Windler E. Greeve J. Levkau B. Kolb-Bachofen V. Daerr W. Greten H. The human asialoglycoprotein receptor is a possible binding site for low-density lipoproteins and chylomicron remnants.Biochem. J. 1991; 276: 79-87Google Scholar), the lipolysis-stimulated receptor (16Bihain B.E. Yen F.T. Free fatty acids activate a high-affinity saturable pathway for degradation of low-density lipoproteins in fibroblasts from a subject homozygous for familial hypercholesterolemia.Biochemistry. 1992; 31: 4628-4636Google Scholar, 17Yen F.T. Mann C.J. Guermani L.M. Hannouche N.F. Hubert N. Hornick C.A. Bordeau V.N. Agnani G. Bihain B.E. Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein.Biochemistry. 1994; 33: 1172-1180Google Scholar, 18Mann C.J. Khallou J. Chevreuil O. Troussard A.A. Guermani L.M. Launay K. Delplanque B. Yen F.T. Bihain B.E. Mechanism of activation and functional significance of the lipolysis-stimulated receptor. Evidence for a role as chylomicron remnant receptor.Biochemistry. 1995; 34: 10421-10431Google Scholar, 19Troussard A.A. Khallou J. Mann C.J. André P. Strickland D.K. Bihain B.E. Yen F.T. Inhibitory effect on the lipolysis-stimulated receptor of the 39-kDa receptor-associated protein.J. Biol. Chem. 1995; 270: 17068-17071Google Scholar), a lactoferrin-inhibited receptor (20van Dijk M.C.M. Ziere G.J. Boers W. Linthorst C. Bijsterbosch M.K. van Berkel T.J.C. Recognition of chylomicron remnants and β-migrating very-low-density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver α2-macroglobulin-recognition site.Biochem. J. 1991; 279: 863-870Google Scholar, 21Ziere G.J. Kruijt J.K. Bijsterbosch M.K. van Berkel T.J.C. Recognition of lactoferrin and aminopeptidase M-modified lactoferrin by the liver: involvement of proteoglycans and the remnant receptor.Biochem. J. 1996; 313: 289-295Google Scholar), and a triglyceride-rich lipoprotein receptor (22Gianturco S.H. Ramprasad M.P. Lin A. H-Y. Song R. Bradley W.A. Cellular binding site and membrane binding proteins for triglyceride-rich lipoproteins in human monocyte-macrophages and THP-1 monocytic cells.J. Lipid Res. 1994; 35: 1674-1687Google Scholar, 23Ramprasad M.P. Li R. Bradley W.A. Gianturco S.H. Human THP-1 monocyte-macrophage membrane binding proteins: distinct receptor(s) for triglyceride-rich lipoproteins.Biochemistry. 1995; 34: 9126-9135Google Scholar), have been postulated to be involved in remnant lipoprotein metabolism. However, their role in this process has not been established. We have hypothesized that remnant lipoprotein metabolism involves three steps. First, remnants are cleared from the plasma by a process involving rapid sequestration of the particles within the space of Disse; heparan sulfate proteoglycans (HSPG) may play a major role in this “capture” step, with apoE and hepatic lipase (HL) serving as important ligands (for review, see refs. 24Mahley R.W. Rall Jr., S.C. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 7th edition. McGraw-Hill, New York1995: 1953-1980Google Scholar, 25Mahley R.W. Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.Isr. J. Med. Sci. 1996; 32: 414-429Google Scholar, 26Plump A.S. Smith J.D. Hayek T. Aalto-Setälä K. Walsh A. Verstuyft J.G. Rubin E.M. Breslow J.L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.Cell. 1992; 71: 343-353Google Scholar, 27Zhang S.H. Reddick R.L. Piedrahita J.A. Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.Science. 1992; 258: 468-471Google Scholar, 28Mahley R.W. Ji Z-S. Brecht W.J. Miranda R.D. He D. Role of heparan sulfate proteoglycans and the LDL receptor-related protein in remnant lipoprotein metabolism.Ann. NY Acad. Sci. 1994; 737: 39-52Google Scholar). Second, remnants may undergo further processing in the space of Disse. We (29Ji Z-S. Lauer S.J. Fazio S. Bensadoun A. Taylor J.M. Mahley R.W. Enhanced binding and uptake of remnant lipoproteins by hepatic lipase-secreting hepatoma cells in culture.J. Biol. Chem. 1994; 269: 13429-13436Google Scholar) and others (30Shafi S. Brady S.E. Bensadoun A. Havel R.J. Role of hepatic lipase in the uptake and processing of chylomicron remnants in rat liver.J. Lipid Res. 1994; 35: 709-720Google Scholar) have demonstrated the importance of HL in this step; other investigators, including Beisiegel, Weber, and Bengtsson-Olivecrona (31Beisiegel U. Weber W. Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein.Proc. Natl. Acad. Sci. USA. 1991; 88: 8342-8346Google Scholar) and Mulder and associates (32Mulder M. Lombardi P. Jansen H. van Berkel T.J.C. Frants R.R. Havekes L.M. Low density lipoprotein receptor internalizes low density and very low density lipoproteins that are bound to heparan sulfate proteoglycans via lipoprotein lipase.J. Biol. Chem. 1993; 268: 9369-9375Google Scholar) have implicated LPL. In vitro studies have shown that the lipases serve as ligands for the HSPG-LRP pathway. Third, uptake of remnants by hepatocytes may be mediated, at least in part, by LDL receptors (33Cooper A.D. Hepatic uptake of chylomicron remnants.J. Lipid Res. 1997; 38: 2173-2192Google Scholar) and, particularly as shown by Herz (11Herz J. The LDL-receptor-related protein—portrait of a multifunctional receptor.Curr. Opin. Lipidol. 1993; 4: 107-113Google Scholar), Krieger and Herz (12Krieger M. Herz J. Structures and functions of multi-ligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).Annu. Rev. Biochem. 1994; 63: 601-637Google Scholar), and Willnow (34Willnow T.E. Mechanisms of hepatic chylomicron remnant clearance.Diabet. Med. 1997; 14: S75-S80Google Scholar), by the LRP. Our studies have shown that HSPG participate not only in the initial sequestration step, but also in the uptake step, either in association with the LRP or acting alone as a receptor (35Ji Z-S. Fazio S. Lee Y-L. Mahley R.W. Secretion–capture role for apolipoprotein E in remnant lipoprotein metabolism involving cell surface heparan sulfate proteoglycans.J. Biol. Chem. 1994; 269: 2764-2772Google Scholar, 36Ji Z-S. Brecht W.J. Miranda R.D. Hussain M.M. Innerarity T.L. Mahley R.W. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells.J. Biol. Chem. 1993; 268: 10160-10167Google Scholar, 37Ji Z-S. Sanan D.A. Mahley R.W. Intravenous heparinase inhibits remnant lipoprotein clearance from the plasma and uptake by the liver: in vivo role of heparan sulfate proteoglycans.J. Lipid Res. 1995; 36: 583-592Google Scholar) (Fig. 1). Recently, Cooper (33Cooper A.D. Hepatic uptake of chylomicron remnants.J. Lipid Res. 1997; 38: 2173-2192Google Scholar) published an extensive review on the hepatic metabolism of chylomicron remnants, summarizing much of the early background and the importance of various ligands. Hussain et al. (38Hussain M.M. Kancha R.K. Zhou Z. Luchoomun J. Zu H. Bakillah A. Chylomicron assembly and catabolism: role of apolipoproteins and receptors.Biochim. Biophys. Acta. 1996; 1300: 151-170Google Scholar) and Willnow (34Willnow T.E. Mechanisms of hepatic chylomicron remnant clearance.Diabet. Med. 1997; 14: S75-S80Google Scholar) have also reviewed this topic recently. Here we focus on the mechanisms responsible for remnant clearance from the plasma and uptake by hepatocytes, especially the importance of cell-surface HSPG. Chylomicron remnants enter the space of Disse through the fenestrated sinusoidal endothelium, which acts as a dynamic biofilter that restricts the entry of large chylomicrons while allowing the smaller remnants to enter (39Fraser R. Dobbs B.R. Rogers G.W.T. Lipoproteins and the liver sieve: the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis.Hepatology. 1995; 21: 863-874Google Scholar). The space of Disse is rich in HSPG and contains an abundance of apoE (40Hamilton R.L. Wong J.S. Guo L.S.S. Krisans S. Havel R.J. Apolipoprotein E localization in rat hepatocytes by immunogold labeling of cryothin sections.J. Lipid Res. 1990; 31: 1589-1603Google Scholar, 41Stow J.L. Kjéllen L. Unger E. Höök M. Farquhar M.G. Heparan sulfate proteoglycans are concentrated on the sinusoidal plasmalemmal domain and in intracellular organelles of hepatocytes.J. Cell Biol. 1985; 100: 975-980Google Scholar) and HL (42Sanan D.A. Fan J. Bensadoun A. Taylor J.M. Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver.J. Lipid Res. 1997; 38: 1002-1013Google Scholar), which are synthesized and secreted by hepatocytes, and LPL, which is presumably carried into the space of Disse on the remnants (43Vilaró S. Ramírez I. Bengtsson-Olivecrona G. Olivecrona T. Llobera M. Lipoprotein lipase in liver. Release by heparin and immunocytochemical localization.Biochim. Biophys. Acta. 1988; 959: 106-117Google Scholar). Apolipoprotein E is critically important and can mediate the sequestration or trapping of the remnants by binding to HSPG (24Mahley R.W. Rall Jr., S.C. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 7th edition. McGraw-Hill, New York1995: 1953-1980Google Scholar, 25Mahley R.W. Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.Isr. J. Med. Sci. 1996; 32: 414-429Google Scholar). The HSPG may thus serve as a reservoir for apoE to enrich the remnant particles. Hepatic lipase may also be bound to the matrix and cell-surface HSPG. The remnant lipoproteins are further processed and then taken up by endocytosis. As illustrated in Fig. 1, we envision three major pathways that are important in remnant lipoprotein uptake by hepatocytes. First, LDL receptors can mediate the direct uptake of remnant lipoproteins, as shown by Choi et al. (44Choi S.Y. Fong L.G. Kirven M.J. Cooper A.D. Use of an anti-low density lipoprotein receptor antibody to quantify the role of the LDL receptor in the removal of chylomicron remnants in the mouse in vivo.J. Clin. Invest. 1991; 88: 1173-1181Google Scholar) and Choi and Cooper (45Choi S.Y. Cooper A.D. A comparison of the roles of the low density lipoprotein (LDL) receptor and the LDL receptor-related protein/α2-macroglobulin receptor in chylomicron remnant removal in the mouse in vivo.J. Biol. Chem. 1993; 268: 15804-15811Google Scholar) and more recently by Ishibashi et al. (46Ishibashi S. Herz J. Maeda N. Goldstein J.L. Brown M.S. The two-receptor model of lipoprotein clearance: tests of the hypothesis in “knockout” mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins.Proc. Natl. Acad. Sci. USA. 1994; 91: 4431-4435Google Scholar), Herz et al. (47Herz J. Qiu S-Q. Oesterle A. de Silva H.V. Shafi S. Havel R.J. Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.Proc. Natl. Acad. Sci. USA. 1995; 92: 4611-4615Google Scholar), Rohlman et al. (48Rohlmann A. Gotthardt M. Hammer R.E. Herz J. Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants.J. Clin. Invest. 1998; 101: 689-695Google Scholar), and Mortimer et al. (49Mortimer B-C. Beveridge D.J. Martins I.J. Redgrave T.C. Intracellular localization and metabolism of chylomicron remnants in the livers of low density lipoprotein receptor-deficient mice and apoE-deficient mice. Evidence for slow metabolism via an alternative apoE-dependent pathway.J. Biol. Chem. 1995; 270: 28767-28776Google Scholar). Second, the HSPG-LRP pathway can mediate uptake either by transfer of the remnants from the HSPG to the LRP for internalization or by binding of the remnant lipoproteins to HSPG forming a tertiary complex with the LRP that is then internalized. The HSPG are critical for the HSPG-LRP pathway because in their absence the remnant do not bind and are not taken up to a major extent by the LRP on the hepatocytes (25Mahley R.W. Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.Isr. J. Med. Sci. 1996; 32: 414-429Google Scholar, 28Mahley R.W. Ji Z-S. Brecht W.J. Miranda R.D. He D. Role of heparan sulfate proteoglycans and the LDL receptor-related protein in remnant lipoprotein metabolism.Ann. NY Acad. Sci. 1994; 737: 39-52Google Scholar, 36Ji Z-S. Brecht W.J. Miranda R.D. Hussain M.M. Innerarity T.L. Mahley R.W. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells.J. Biol. Chem. 1993; 268: 10160-10167Google Scholar). Third, HSPG alone can mediate remnant lipoprotein uptake and function as a receptor. Each of these pathways will be discussed. Several approaches have shown that apoE is a critical ligand for the clearance of remnant lipoproteins. Years ago, we demonstrated that the intravenous infusion of apoE reduces remnant lipoproteins in cholesterol-fed rabbits, a model characterized by substantial accumulation of these particles in the plasma (50Mahley R.W. Weisgraber K.H. Hussain M.M. Greenman B. Fisher M. Vogel T. Gorecki M. Intravenous infusion of apolipoprotein E accelerates clearance of plasma lipoproteins in rabbits.J. Clin. Invest. 1989; 83: 2125-2130Google Scholar). Within 2–3 h after intravenous infusion of 6–12 mg of apoE, the plasma cholesterol levels decreased by 35–40%. The apoE drove the remnants into the liver. In transgenic mice expressing rat apoE, the apoE was localized to the sinusoids, presumably reflecting distribution in the space of Disse; after infusion of remnant lipoproteins, the apoE appeared to be distributed over the hepatic parenchymal cells and decreased in the sinusoids (51Shimano H. Namba Y. Ohsuga J. Kawamura M. Yamamoto K. Shimada M. Gotoda T. Harada K. Yazaki Y. Yamada N. Secretion–recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.J. Clin. Invest. 1994; 93: 2215-2223Google Scholar). More recently, Fan and colleagues (52Fan J. Ji Z-S. Huang Y. de Silva H. Sanan D. Mahley R.W. Innerarity T.L. Taylor J.M. Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma.J. Clin. Invest. 1998; 101: 2151-2164Google Scholar) demonstrated that overexpression of human apoE in transgenic rabbits prevented diet-induced remnant accumulation and also accelerated remnant lipoprotein clearance from the plasma (Fig. 2). The accelerated clearance was accounted for by the uptake of remnants within the liver. Studies of patients with type III hyperlipoproteinemia also implicate apoE as a critical ligand for remnant metabolism (for review, see refs. 3Mahley R.W. Weisgraber K.H. Farese Jr., R.V. Disorders of lipid metabolism.in: Wilson J.D. Foster D.W. Kronenberg H.M. Larsen P.R. Williams Textbook of Endocrinology. 9th edition. W.B. Saunders, Philadelphia1998: 1099-1153Google Scholar, 24Mahley R.W. Rall Jr., S.C. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 7th edition. McGraw-Hill, New York1995: 1953-1980Google Scholar, 25Mahley R.W. Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.Isr. J. Med. Sci. 1996; 32: 414-429Google Scholar). This genetic disease is characterized by impaired remnant lipoprotein clearance as a result of various mutant forms of apoE that are defective in binding to lipoprotein receptors. All of these variants are associated with the development of the hyperlipidemia, and the mutant apoE correlates with defective clearance of remnant lipoproteins. The mutations of apoE that cause defective binding occur primarily in or near the receptor-binding domain, the region encompassing amino acids 136–150 (53Fazio S. Lee Y-L. Ji Z-S. Rall Jr., S.C. Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E.J. Clin. Invest. 1993; 92: 1497-1503Google Scholar). One interesting variant we have studied is apoE (Arg142→Cys), in which the arginine at residue 142 is replaced with a cysteine (54Rall Jr., S.C. Newhouse Y.M. Clarke H.R.G. Weisgraber K.H. McCarthy B.J. Mahley R.W. Bersot T.P. Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant.J. Clin. Invest. 1989; 83: 1095-1101Google Scholar, 55Horie Y. Fazio S. Westerlund J.R. Weisgraber K.H. Rall Jr., S.C. The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia.J. Biol. Chem. 1992; 267: 1962-1968Google Scholar). This variant is associated with the dominant transmission of the disease, causing hyperlipidemia at birth, marked remnant accumulation, and premature atherosclerosis. The apoE(Arg142→Cys) variant exhibits 20% of normal binding to the LDL receptor and less than 5% of normal binding to the LRP and to HSPG (55Horie Y. Fazio S. Westerlund J.R. Weisgraber K.H. Rall Jr., S.C. The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia.J. Biol. Chem. 1992; 267: 1962-1968Google Scholar). Expression of apoE(Arg142→Cys) in transgenic mice demonstrated that this mutant protein was responsible for the impaired remnant metabolism. In these mice, Fazio et al. (53Fazio S. Lee Y-L. Ji Z-S. Rall Jr., S.C. Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E.J. Clin. Invest. 1993; 92: 1497-1503Google Scholar) showed that overexpression of the 142 variant resulted in a hyperlipidemia characterized by β-VLDL remnants. The mice had a hypercholesterolemia of 307 mg/dl and a hypertriglyceridemia of 378 mg/dl. These lipid levels are similar to those in patients with the apoE(Arg142→ Cys) variant. The apoE(Arg142→Cys) transgenic mice had an increase in the VLDL fraction, specifically in the remnant lipoproteins. By comparison, the nontransgenic control mice had virtually undetectable levels of remnants in their plasma. Clearly, the binding-defective apoE results inimpaired remnant clearance (the mechanism will be discussed in detail later). Plump et al. (26Plump A.S. Smith J.D. Hayek T. Aalto-Setälä K. Walsh A. Verstuyft J.G. Rubin E.M. Breslow J.L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.Cell. 1992; 71: 343-353Google Scholar) and Zhang et al. (27Zhang S.H. Reddick R.L. Piedrahita J.A. Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.Science. 1992; 258: 468-471Google Scholar) created apoE knockout mice that display very severe hypercholesterolemia characterized by marked accumulation of remnants, again indicating a critical role of apoE in remnant" @default.
• W2150436995 created "2016-06-24" @default.
• W2150436995 creator A5036108557 @default.
• W2150436995 creator A5067737380 @default.
• W2150436995 date "1999-01-01" @default.
• W2150436995 modified "2023-10-14" @default.
• W2150436995 title "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E" @default.
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