Title: Hepatic Catabolism of Remnant Lipoproteins: Where the Action Is
Abstract: HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 24, No. 2Hepatic Catabolism of Remnant Lipoproteins: Where the Action Is Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHepatic Catabolism of Remnant Lipoproteins: Where the Action Is Richard J. Havel and Robert L. Hamilton Richard J. HavelRichard J. Havel From the Cardiovascular Research Institute (R.J.H., R.L.H.) and the Department of Anatomy (R.L.H.), University of California San Francisco, CA. and Robert L. HamiltonRobert L. Hamilton From the Cardiovascular Research Institute (R.J.H., R.L.H.) and the Department of Anatomy (R.L.H.), University of California San Francisco, CA. Originally published1 Feb 2004https://doi.org/10.1161/01.ATV.0000115382.53810.24Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:213–215is corrected byCorrectionCorrectionBrown and Goldstein described the classical pathway of low-density lipoprotein (LDL) catabolism in human fibroblasts, initiated by LDL-binding to the LDL receptor (LDLR) and followed by endocytosis and lysosomal catabolism of its components.1 The initial steps in the hepatic catabolism of chylomicron remnants and large very-low-density lipoprotein (VLDL) remnants have turned out to be more complex, involving initial binding to other cell surface molecules, including heparan sulfate proteoglycans (HSPGs), apo E, and hepatic lipase (HL), followed by transfer to endocytic receptors (LDLR and LDLR-related protein [LRP]).2 Apo E was first demonstrated on hepatocyte surfaces in rat liver.3 At the light microscopic level, the bulk of hepatic apo E was in the space of Disse. At the electron microscopic level, this apo E was found exclusively on microvilli, occasionally associated with an evident lipoprotein particle. Virtually no apo E was in the electron-lucent matrix. HL is also associated mainly with basolateral microvilli of hepatocytes in rat liver4 and in rabbit liver transfected with human HL.5 Apo E-deficient mice are dysbetalipoproteinemic, with massive accumulation of remnants in the blood.6 In mice doubly deficient in apo E and HL, accumulation of lipoproteins in the blood is even greater and includes vesicular lipoproteins, suggesting further impairment of endocytosis, together with selective uptake of cholesteryl esters, presumably by scavenger receptor B1.7See page 91 and coverThe location of the primary binding sites for remnants on microvilli makes sense because these tiny finger-like projections are the first cellular structures that remnants encounter after they enter the space of Disse via the fenestrae (≈100 to 200 nm diameter) of endothelial cells that line hepatic sinusoids. Wisse et al have postulated a dynamically active space of Disse undergoing forced sieving of lipoprotein particles through a process of sinusoidal "endothelial massage" by compression from bypassing blood cells.8 It is not widely appreciated that LDLR and LRP are also associated with the basolateral microvilli of rat hepatocytes.9,10 Thus, initial binding of remnant particles and their subsequent endocytosis involve several macromolecules located on the plasma membrane of hepatocytic microvilli (Figure). Because endocytosis presumably occurs by invagination of coated pits at the base of microvilli, remnant lipoproteins must migrate there together with these receptors along the plane of the microvillar membrane. Download figureDownload PowerPointTop left, Receptor-mediated uptake and intracellular processing of triglyceride-rich remnants and cholesteryl ester-rich LDL in rat liver (1988 version), showing passage of lipoproteins through fenestrae in the sinusoidal endothelium, followed by binding to endocytic receptors (Y) on hepatocytic microvilli projecting into the space of Disse (SD). The endocytic receptors migrate with their cargo to coated pits at the microvillar bases where they undergo endocytosis to form primary endosomes. After loss of the clathrin coat and endosome-fusion, the lipoproteins dissociate from the receptors at the acidic pH within the endosome. The lipoproteins are transported within the maturing endosomes toward the biliary (apical) pole of the cells, forming multivesicular bodies (MVB) (late endosomes), whereas the excess surface membrane resulting from endosome-fusion forms recycling endosomes that carry the receptors back to the basolateral surface of the cell (modified from Figure 1 in Havel RJ, Hamilton RL. Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism. Hepatology. 1988;8:1689–1704.). Top right (2003 version), Enlargement of a basolateral microvillus and adjacent endothelial cell (E), showing that chylomicron and large VLDL remnants pass through endothelial cell-fenestrae to the space of Disse where they bind initially to proteoglycan-bound apo E and hepatic lipase as well as LDLR, all of which are anchored to the microvillar membrane. Proteoglycan-bound hepatic lipase binds and hydrolyzes remnant-lipids, increasing exposure of the endocytic receptor-binding domain of apo E. Hepatic lipase can also act as a ligand for the endocytic receptors. Additional proteoglycan-bound apo E on microvilli acquired by the remnants increases the affinity of the remnant particles for LRP. The extent to which proteoglycans, hepatic lipase, and surface apo E themselves undergo endocytosis with the remnant particles is unknown. Normally, the surface density of LRP greatly exceeds that of LDLR, but only LDLR can readily bind remnants without further modification in the space of Disse. Bottom left, Thin section electron micrograph of normal rat liver illustrating the basolateral surface of hepatocytes (H) projecting numerous microvilli into the space of Disse. Plasma, including lipoproteins up to ≈200 nm diameter in the sinusoid, exchanges freely with the space of Disse through fenestrae (arrows) in the endothelium (E). ×18 000 diameters. Bottom right, Ultracryothin section of normal rat hepatocyte space of Disse showing microvilli decorated with 5-nm colloidal gold complexed with affinity-purified rabbit polyclonal anti-LRP from rat liver.10 ×90 000 diameters.Both HL and apo E are thought to be bound to the surface of liver cells by HSPGs.11,12 Although heparin releases some apo E from cell surfaces in rat liver, heparin is much less effective in releasing apo E as compared with the negatively charged polyelectrolyte, suramin.11 Some cell surface apo E may be bound to LRP or LDLR, for which it is a high-affinity ligand. In this regard, suramin, but not heparin, can release α2-macroglobulin from its high-affinity binding to LRP.13 In human hepatoma cells, surface apo E is bound not only to HSPGs but also to chondroitin sulfate proteoglycans in an even larger fraction.14 Moreover, in these cultured cell monolayers, ≈one-third the apo E associated with these cells is bound to HSPGs of the underlying matrix rather than to the cell surface.15 Whether such binding of apo E applies to hepatocytes in vivo is unknown.Unlike rodent apo E, human apo E is polymorphic with 3 alleles that code for apo E2, E3, and E4.16 As compared with the most common isoform (apo E3), apo E2 has strikingly reduced affinity for LDLR and moderately reduced affinity for LRP, whereas apo E4 has somewhat increased affinity for LDLR and comparable affinity for LRP.17,18 Apo E2 homozygotes express a dyslipoproteinemic phenotype with accumulation of chylomicron and VLDL remnants but usually have low concentrations of LDL, whereas apo E4 homozygotes have somewhat higher levels of LDL.19,20 The latter phenotype is generally thought to reflect downregulation of the hepatic LDLR caused by enhanced uptake of VLDL remnants.17,20The distinct effects of human apo E isoforms on lipoprotein metabolism have been the subject of elegant studies by Maeda et al at the University of North Carolina. They have generated mice that express human apo E2, apo E3, or apo E4 in a physiologically regulated manner by replacing the coding sequences of the mouse apo ε2 gene with each of the 3 human alleles.18,21–23 Mice expressing human apo E2 are dyslipoproteinemic.22 When the apo E2 mice were bred with mice expressing a human LDLR minigene regulated by the endogenous mouse promoter but modified to increase mRNA stability, the resulting increased LDLR expression corrected the dysbetalipoproteinemia, as expected.23 Contrary to expectation, however, Knouff et al found that VLDL levels were doubled and rates of VLDL clearance were halved in mice expressing apo E4 as compared with those observed in mice expressing apo E3.18 Because the delayed clearance could not be explained by alterations of the VLDL particles, they postulated that it reflected intrinsic differences in the animals themselves, perhaps related to altered interactions with the "hepatic microenvironment."In a recent report in this journal, Malloy et al have tested this hypothesis in apo E4 and apo E3 mice crossbred with mice expressing the human LDL receptor minigene, as in the earlier studies with human apo E2 mice.24 Once again, the results were unexpected. When the animals were fed cholesterol- and fat-rich diet, the apo E4 mice, but not apo E3 mice, had pronounced hypercholesterolemia because of accumulation of cholesterol-rich, but triglyceride- and apo E-poor, remnants. These particles contained mainly apo B-48 and apo A-IV, but little apo E, and their concentration decreased profoundly after a 12-hour fast, suggestive of an intestinal rather than hepatic origin. Apo E concentrations were comparably reduced in plasma but increased in liver in the crossbred apo E4 and apo E3 mice. Other data suggested that chylomicron secretion and hepatic VLDL production were unaltered in apo E4 mice. Despite the increased expression of hepatic LDLRs, the apo E4 mice did not clear radiolabeled VLDL from apo E-deficient mice faster than mice expressing apo E4 but lacking the human LDL receptor minigene, but they did clear apo E-enriched radiolabeled VLDL at a more rapid rate. Apo E is transferred from HDL to nascent triglyceride-rich lipoproteins, particularly those from the intestine,25 rendering the particles competent to bind to endocytic receptors. It has also been proposed that further enrichment occurs in the space of Disse through acquisition of surface apo E from hepatocytes.3,26 Malloy et al propose the novel hypothesis that apo E4 becomes "trapped" in the liver to a greater extent than apo E3 because of its increased affinity for LDLR.24 As a result, postprandial triglyceride-rich lipoproteins, which remain deficient in apo E, could be readily converted to remnants by lipoprotein lipase but would have low affinity for hepatic lipoprotein receptors. This is consistent with the observed accumulation of remnants deficient in triglycerides and apo E in the apo E4 mice expressing increased levels of LDLR.How might the postulated "trapping" take place? HDL that contain apo E are taken-up rapidly by the liver of rats treated with 17-α-ethinyl estradiol, which induces high expression of hepatic LDLRs.27 Cell surface apo E may also be endocytosed more rapidly under conditions of increased LDLR expression. Other possibilities should be considered. In rat liver, apo E is abundant in multivesicular bodies.3 These late endosomes are the immediate prelysosomal compartment (Figure).9 Furthermore, in perfused rat livers, labeled apo E bound to VLDL or HDL is extensively degraded to soluble products.28,29 However, we have observed substantial immunoreactive apo E not only within multivesicular bodies but also in recycling endosomes isolated from rat livers (RL Hamilton and RJ Havel, unpublished data). Furthermore, several investigators have shown that lipoprotein-bound apo E taken-up into rodent livers is partially resecreted, although the precise pathways involved are uncertain.30 Resecretion of apo E could contribute to the pool of cell-surface apo E, and the extent of resecretion might vary among its isoforms. Of interest in this regard, uptake of apo E4-enriched VLDL by a neuronal cell line caused lesser intracellular accumulation of apo E than that observed with apo E3-enriched VLDL.31In their article, Malloy et al cite studies of postprandial lipemia in normolipidemic humans by Bergeron et al, which indicated prolonged residence times of triglyceride-rich lipoproteins particles containing apo B-48 and apo B-100 in apo E 4/3 heterozygotes as compared with apo E3 homozygotes.32 Bergeron et al suggested that apo E on chylomicron remnants of persons with an apo E4/3 phenotype may be less accessible to hepatic lipoprotein receptors than apo E in those persons with an apo E3/3 phenotype. They proposed that consequent increased conversion of VLDL (containing apo B-100) to LDL might cause the increased LDL levels observed in apo E4/3 heterozygotes. As Malloy et al point out, this proposal is consistent with kinetic studies in E4/4 homozygotes indicating reduced direct removal of VLDL remnants accompanied by increased conversion of VLDL to smaller particles.33 In the studies of Bergeron et al, however, there was no evidence that the remnants that accumulated postprandially in apo E4/3 heterozygotes were depleted of apo Es.32 Accordingly, the trapping hypothesis per se may not fully explain the human apo E4 phenotype.The microvilli in the space of Disse clearly provide a nexus for complex interactions among the players identified in the uptake, endocytosis, and intracellular processing of remnant lipoproteins. The heuristic observations of Malloy et al and their apo E-trapping hypothesis should stimulate further studies of these interactions and the influence of apo E isoforms in remnant catabolism.FootnotesCorrespondence to Richard J. Havel, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94943-0130. E-mail [email protected] References 1 Brown MS, Goldstein, JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986; 232: 34–47.CrossrefMedlineGoogle Scholar2 Herz J, Qiu S-Q, Oesterle A, DeSilva HV, Shafi S, Havel RJ. Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low-density lipoprotein receptor. Proc Natl Acad Sci U S A. 1995; 92: 4611–4615.CrossrefMedlineGoogle Scholar3 Hamilton RL, Wong JS, Guo LSS, Krisans S, Havel RJ. Apolipoprotein E localization in rat hepatocytes by immunogold labeling of cryothin sections. J Lipid Res. 1991; 31: 1589–1603.Google Scholar4 Breedveld B, Schoonderwoerd K, Verhoeven AJM, Willemsen R, Jansen H. Hepatic lipase is localized at the parenchymal cell microvilli in rat liver. Biochem J. 1997; 321: 425–430.CrossrefMedlineGoogle Scholar5 Sanan DA, Fan J, Bensadoun A, Taylor JM. Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver. J Lipid Res. 1997; 38: 1002–1013.CrossrefMedlineGoogle Scholar6 Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacing apolipoprotein E. Science. 1992; 258: 468–471.CrossrefMedlineGoogle Scholar7 Bergeron N, Kotite L, Vergés M, Blanche P, Hamilton RL, Krauss RM, Bensadoun A, Havel RJ. Lamellar lipoproteins uniquely contribute to hyperlipidemia in mice doubly deficient in apolipoprotein E and hepatic lipase. Proc Natl Acad Sci U S A. 1998; 95: 15647–15652.CrossrefMedlineGoogle Scholar8 Wisse E, De Zanger RB, Charels K, Van Der Smissen P, McCuskey RS. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology. 1985; 5: 683–692.CrossrefMedlineGoogle Scholar9 Havel RJ, Hamilton RL. Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism. Hepatology. 1988; 8: 1689–1704.CrossrefMedlineGoogle Scholar10 Lund H, Takahashi K, Hamilton RL, Havel RJ. Lipoprotein binding and endosomal itinerary of the low density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 1989; 86: 9318–9322.CrossrefMedlineGoogle Scholar11 Shafi S, Brady SE, Bensadoun A, Havel RJ. Role of hepatic lipase in the uptake and processing of chylomicron remnants in rat liver. J Lipid Res. 1994; 25: 709–720.Google Scholar12 Schoonderwoerd K, Verhoeven AJ. Jansen H. Rat liver contains a limited number of binding sites for hepatic lipase. Biochem J. 1994; 302: 717–722.CrossrefMedlineGoogle Scholar13 Vassiliou G, Stanley KK. Exogenous receptor-associated protein binds to two distinct sites on human fibroblasts but does not bind to the glycosaminoglycan residues of heparan sulfate proteoglycans. J Biol Chem. 1994; 269: 15172–15178.CrossrefMedlineGoogle Scholar14 Burgess JW, Liang P, Vaidyanath C, Marcel YL. ApoE of the hepG2 cell surface includes a major pool associated with chondroitin sulfate proteoglycans. Biochem. 1999; 38: 524–531.CrossrefMedlineGoogle Scholar15 Burgess JW, Gould DR, Marcel YL. The hepG2 extracellular matrix contains separate heparinase- and lipid-releasable pools of apoE. J Biol Chem. 1998; 273: 5645–5654.CrossrefMedlineGoogle Scholar16 Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel JH, Csázár A, Utermann G. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Am J Human Genet. 1991; 49: 338–349.MedlineGoogle Scholar17 Mamotte C, Cyril DS, Sturm M, Foo JI, Van Bockxmeer FM, Taylor RR. Comparison of the LDL-receptor binding of VLDL and LDL from apoE4 and apoE3 homozygotes. Am J Physiol (Endocrinol Metab 39). 1999; 276: E553–E557.CrossrefMedlineGoogle Scholar18 Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest. 1999; 103: 1579–1586.CrossrefMedlineGoogle Scholar19 Mahley RW, Rall Jr CS. Type III hyperlipoproteinemia (dysbetalipoproteinemia). The role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: ALScriver, WSSly, DValle, eds. The Metabolic and Molecular Bases of Inheritable Disease. New York: McGraw Hill; 2001:2835–2913.Google Scholar20 Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988; 8: 1–21.LinkGoogle Scholar21 Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N. Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem. 1997; 272: 17972–17980.CrossrefMedlineGoogle Scholar22 Sullivan PM, Mezdour H, Quarfordt SH, Maeda N. Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse apo E with human APO E2. J Clin Invest. 1998; 102: 130–135.CrossrefMedlineGoogle Scholar23 Knouff C, Malloy S, Wilder J, Altenburg MK, Maeda N. Doubling expression of the low density lipoprotein receptor by truncation of the 3′-untranslated region sequence ameliorates type III hyperlipoproteinemia in mice expressing the human apoE2 isoform. J Biol Chem. 2001; 276: 3856–3862.CrossrefMedlineGoogle Scholar24 Malloy SI, Altenburg MK, Knouff C, Lanningham-Foster L, Parks JS, Maeda N. Harmful effects of increased LDLR expression in mice with human APOE4 but not APOE3. Arterioscler Thromb Vasc Biol. 2004; 24: 91–97.LinkGoogle Scholar25 Imaizumi K, Fainaru M, Havel RJ. Composition of proteins of mesenteric lymph chylomicrons in the rat and alterations produced upon exposure of chylomicrons to blood serum and serum proteins. J Lipid Res. 1978; 19: 712–722.CrossrefMedlineGoogle Scholar26 Brown MS, Herz J, Kowal RC, Goldstein JL. The low-density lipoprotein receptor-related protein: double agent or decoy? Curr Opin Lipidol. 1991; 2: 65–72.CrossrefGoogle Scholar27 Chao Y-S, Windler EE, Chi Chen G, Havel RJ. Hepatic catabolism of rat and human lipoproteins in rats treated with 17α-ethinyl estradiol. J Biol Chem. 1979; 254: 11360–11366.CrossrefMedlineGoogle Scholar28 van't Hooft F, Havel RJ. Metabolism of chromatographically separated rat serum lipoproteins specifically labeled with 125I-apolipoprotein E. J Biol Chem. 1981; 256: 3963–3968.CrossrefMedlineGoogle Scholar29 van't Hooft F, Havel RJ. Metabolism of apolipoprotein E in plasma high density lipoproteins from normal and cholesterol-fed rats. J Biol Chem. 1982; 257: 10996–11001.CrossrefMedlineGoogle Scholar30 Heeren J, Beisiegel U. Intracellular metabolism of triglyceride-rich lipoproteins. Curr Opin Lipidol. 2001; 12: 255–260.CrossrefMedlineGoogle Scholar31 Ji Z-S, Pitas RE, Mahley RW. Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. J Biol Chem. 1998; 273: 13452–13460.CrossrefMedlineGoogle Scholar32 Bergeron N, Havel RJ. Prolonged postprandial responses of lipids and apolipoproteins in triglyceride-rich lipoproteins of individuals expressing an apolipoprotein ε4 allele. J Clin Invest. 1996; 97: 65–72.CrossrefMedlineGoogle Scholar33 Demant T, Bedford D, Packard CJ, Shepherd J. Influence of apolipoprotein E polymorphism on apolipoprotein B-100 metabolism in normolipemic subjects. J Clin Invest. 1991; 88: 1490–1501.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Singh A, Chaube B, Zhang X, Sun J, Citrin K, Canfrán-Duque A, Aryal B, Rotllan N, Varela L, Lee R, Horvath T, Price N, Suárez Y and Fernández-Hernando C (2021) Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice, Journal of Clinical Investigation, 10.1172/JCI140989, 131:17, Online publication date: 1-Sep-2021., Online publication date: 1-Sep-2021. Stahel P, Xiao C, Nahmias A, Tian L and Lewis G (2021) Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks, Endocrine Reviews, 10.1210/endrev/bnab008, 42:6, (815-838), Online publication date: 16-Nov-2021. Schade D, Shey L and Eaton R (2020) Cholesterol Review: A Metabolically Important Molecule, Endocrine Practice, 10.4158/EP-2020-0347, 26:12, (1514-1523), Online publication date: 1-Dec-2020. Hodson L and Gunn P (2019) The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state, Nature Reviews Endocrinology, 10.1038/s41574-019-0256-9, 15:12, (689-700), Online publication date: 1-Dec-2019. Green C, Parry S, Gunn P, Ceresa C, Rosqvist F, Piché M and Hodson L Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models, Hormone Molecular Biology and Clinical Investigation, 10.1515/hmbci-2018-0038, 0:0 Parry S and Hodson L (2017) Influence of dietary macronutrients on liver fat accumulation and metabolism, Journal of Investigative Medicine, 10.1136/jim-2017-000524, 65:8, (1102-1115), Online publication date: 1-Dec-2017. Wolf Greenstein A, Majumdar N, Yang P, Subbaiah P, Kineman R and Cordoba-Chacon J Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice, Journal of Endocrinology, 10.1530/JOE-16-0447, 232:1, (107-121) Mooij H, Bernelot Moens S, Gordts P, Stanford K, Foley E, van den Boogert M, Witjes J, Hassing H, Tanck M, van de Sande M, Levels J, Kastelein J, Stroes E, Dallinga-Thie G, Esko J and Nieuwdorp M (2015) Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans, Journal of Lipid Research, 10.1194/jlr.M053504, 56:3, (665-673), Online publication date: 1-Mar-2015. Rolim A, Henrique-Araújo R, Ferraz E, de Araújo Alves Dultra F and Fernandez L (2015) Lipidomics in the study of lipid metabolism: Current perspectives in the omic sciences, Gene, 10.1016/j.gene.2014.10.039, 554:2, (131-139), Online publication date: 1-Jan-2015. Zhou L, Yang H, Okoro E and Guo Z (2014) Up-regulation of Cholesterol Absorption Is a Mechanism for Cholecystokinin-induced Hypercholesterolemia, Journal of Biological Chemistry, 10.1074/jbc.M113.534388, 289:19, (12989-12999), Online publication date: 1-May-2014. Adepu S, Katta K, Tietge U, Kwakernaak A, Dam W, van Goor H, Dullaart R, Navis G, Bakker S and van den Born J (2014) Hepatic Syndecan-1 Changes Associate With Dyslipidemia After Renal Transplantation, American Journal of Transplantation, 10.1111/ajt.12842, 14:10, (2328-2338), Online publication date: 1-Oct-2014. Hassing H, Surendran R, Mooij H, Stroes E, Nieuwdorp M and Dallinga-Thie G (2012) Pathophysiology of hypertriglyceridemia, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 10.1016/j.bbalip.2011.11.010, 1821:5, (826-832), Online publication date: 1-May-2012. Adiels M, Matikainen N, Westerbacka J, Söderlund S, Larsson T, Olofsson S, Borén J and Taskinen M (2012) Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity, Atherosclerosis, 10.1016/j.atherosclerosis.2012.02.001, 222:1, (222-228), Online publication date: 1-May-2012. Jun J, Ma Z and Segar L (2011) Spontaneously diabetic Ins2 +/Akita :apoE-deficient mice exhibit exaggerated hypercholesterolemia and atherosclerosis , American Journal of Physiology-Endocrinology and Metabolism, 10.1152/ajpendo.00034.2011, 301:1, (E145-E154), Online publication date: 1-Jul-2011. Jacobs F, Van Craeyveld E, Feng Y and De Geest B (2011) The diameter of liver sinusoidal fenestrae is not a major determinant of lipoprotein levels and atherosclerosis in cholesterol-fed rabbits, Cardiovascular Pathology, 10.1016/j.carpath.2009.09.002, 20:1, (44-50), Online publication date: 1-Jan-2011. Havel R (2010) Triglyceride-Rich Lipoproteins and Plasma Lipid Transport, Arteriosclerosis, Thrombosis, and Vascular Biology, 30:1, (9-19), Online publication date: 1-Jan-2010. Hodson L and Fielding B (2017) Trafficking and partitioning of fatty acids: the transition from fasted to fed state, Clinical Lipidology, 10.2217/clp.09.72, 5:1, (131-144), Online publication date: 1-Feb-2010. Foley E and Esko J (2010) Hepatic Heparan Sulfate Proteoglycans and Endocytic Clearance of Triglyceride-Rich Lipoproteins Glycosaminoglycans in Development, Health and Disease, 10.1016/S1877-1173(10)93010-X, (213-233), . Bruns O, Ittrich H, Peldschus K, Kaul M, Tromsdorf U, Lauterwasser J, Nikolic M, Mollwitz B, Merkel M, Bigall N, Sapra S, Reimer R, Hohenberg H, Weller H, Eychmüller A, Adam G, Beisiegel U and Heeren J (2009) Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals, Nature Nanotechnology, 10.1038/nnano.2008.405, 4:3, (193-201), Online publication date: 1-Mar-2009. Santos R (2009) Commentary on the study of Laatsch et al. "Insulin stimulates hepatic low density lipoprotein receptor-related protein 1 (LRP1) to increase postprandial lipoprotein clearance", Atherosclerosis, 10.1016/j.atherosclerosis.2008.10.018, 204:1, (112-113), Online publication date: 1-May-2009. Heeren J and Beisiegel U (2009) Receptor-Mediated Endocytosis and Intracellular Trafficking of Lipoproteins Cellular Lipid Metabolism, 10.1007/978-3-642-00300-4_8, (213-235), . Babin P and Gibbons G (2009) The evolution of plasma cholesterol: Direct utility or a "spandrel" of hepatic lipid metabolism?, Progress in Lipid Research, 10.1016/j.plipres.2008.11.002, 48:2, (73-91), Online publication date: 1-Mar-2009. Laatsch A, Merkel M, Talmud P, Grewal T, Beisiegel U and Heeren J (2009) Insulin stimulates hepatic low density lipoprotein receptor-related protein 1 (LRP1) to increase postprandial lipoprotein clearance, Atherosclerosis, 10.1016/j.atherosclerosis.2008.07.046, 204:1, (105-111), Online publication date: 1-May-2009. Matsumoto K, Miki R, Nakayama M, Tatsumi N and Yokouchi Y (2008) Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium, Developmental Biology, 10.1016/j.ydbio.2008.04.021, 319:2, (234-247), Online publication date: 1-Jul-2008. Georgescu E (2008) Angiotensin receptor blockers in the treatment of NASH/NAFLD: Could they be a first-class option?, Advances in Therapy, 10.1007/s12325-008-0110-2, 25:11, (1141-1174), Online publication date: 1-Nov-2008. Hofmann S, Perez-Tilve D, Greer T, Coburn B, Grant E, Basford J, Tschöp M and Hui D (2008) Defective Lipid Delivery Modulates Glucose Tolerance and Metabolic Response to Diet in Apolipoprotein E–Deficient Mice, Diabetes, 10.2337/db07-0403, 57:1, (5-12), Online publication date: 1-Jan-2008. Bishop J, Stanford K and Esko J (2008) Heparan sulfate proteoglycans and triglyceride-rich lipoprotein metabolism, Current Opinion in Lipidology, 10.1097/MOL.0b013e3282feec2d, 19:3, (307-313), Online publication date: 1-Jun-2008. Hodson L, Bickerton A, McQuaid S, Roberts R, Karpe F, Frayn K and Fielding B (2007) The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women, Diabetes, 10.2337/db07-0654, 56:10, (2433-2441), Online publication date: 1-Oct-2007. Wu D, Sharan C, Yang H, Goodwin J, Zhou L, Grabowski G, Du H and Guo Z (2007) Apolipoprotein E-deficient lipoproteins induce foam cell formation by downregulation of lysosomal hydrolases in macrophages, Journal of Lipid Research, 10.1194/jlr.M700217-JLR200, 48:12, (2571-2578), Online publication date: 1-Dec-2007. MacArthur J, Bishop J, Stanford K, Wang L, Bensadoun A, Witztum J and Esko J (2007) Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members, Journal of Clinical Investigation, 10.1172/JCI29154, 117:1, (153-164), Online publication date: 2-Jan-2007. Collin P, Chapados N, Dufresne E, Corriveau P, Imbeault P and Lavoie J (2007) Time course of changes in in vitro lipolysis of intra-abdominal fat depots in relation to high-fat diet-induced hepatic steatosis in rats , British Journal of Nutrition, 10.1079/BJN20061775, 96:2, (268-275), Online publication date: 1-Aug-2006. Wu D, Yang H, Xiang W, Zhou L, Shi M, Julies G, LaPlante J, Ballard B and Guo Z (2005) Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice, Journal of Lipid Research, 10.1194/jlr.M400430-JLR200, 46:7, (1380-1387), Online publication date: 1-Jul-2005. Carpenter B, Lin Y, Stoll S, Raffai R, McCuskey R and Wang R (2005) VEGF is crucial for the hepatic vascular development required for lipoprotein uptake, Development, 10.1242/dev.01902, 132:14, (3293-3303), Online publication date: 15-Jul-2005. Donnelly K, Smith C, Schwarzenberg S, Jessurun J, Boldt M and Parks E (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease, Journal of Clinical Investigation, 10.1172/JCI23621, 115:5, (1343-1351), Online publication date: 2-May-2005. Hilmer S, Cogger V, Fraser R, McLean A, Sullivan D and Le Couteur D (2005) Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat, Hepatology, 10.1002/hep.20937, 42:6, (1349-1354), Online publication date: 1-Dec-2005. Wouters K, Shiri-Sverdlov R, van Gorp P, van Bilsen M and Hofker M Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice, Clinical Chemistry and Laboratory Medicine (CCLM), 10.1515/CCLM.2005.085, 43:5 TRABER M, BURTON G and HAMILTON R (2004) Vitamin E Trafficking, Annals of the New York Academy of Sciences, 10.1196/annals.1331.001, 1031:1, (1-12), Online publication date: 1-Dec-2004. Saito H, Lund-Katz S and Phillips M (2004) Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins, Progress in Lipid Research, 10.1016/j.plipres.2004.05.002, 43:4, (350-380), Online publication date: 1-Jul-2004. Laatsch A, Panteli M, Sornsakrin M, Hoffzimmer B, Grewal T, Heeren J and Johannes L (2012) Low Density Lipoprotein Receptor-Related Protein 1 Dependent Endosomal Trapping and Recycling of Apolipoprotein E, PLoS ONE, 10.1371/journal.pone.0029385, 7:1, (e29385) Zhou L, Yang H, Lin X, Okoro E, Guo Z and Romanovsky A (2012) Cholecystokinin Elevates Mouse Plasma Lipids, PLoS ONE, 10.1371/journal.pone.0051011, 7:12, (e51011) Gambino R, Bugianesi E, Rosso C, Mezzabotta L, Pinach S, Alemanno N, Saba F and Cassader M (2016) Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat Load, International Journal of Molecular Sciences, 10.3390/ijms17040479, 17:4, (479) Related articlesCorrectionArteriosclerosis, Thrombosis, and Vascular Biology. 2018;38:e59-e59CorrectionArteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:618-618 February 2004Vol 24, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000115382.53810.24PMID: 14766735 Originally publishedFebruary 1, 2004 PDF download Advertisement
Publication Year: 2004
Publication Date: 2004-02-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 59
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