Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

Mahley, Robert W.; Ji, Zhong-Sheng

doi:10.1016/s0022-2275(20)33334-4

Cited by 693Lipid metabolism and disordersCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

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Mahley, Robert W., Ji, Zhong-Sheng·1999·Journal of Lipid Research

DOI 10.1016/s0022-2275(20)33334-4

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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.

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Hepatic lipase mediates the uptake of chylomicrons and beta-VLDL into cells via the LDL receptor-related protein (LRP)
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Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein
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Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor
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Initial hepatic removal of chylomicron remnants is unaffected but endocytosis is delayed in mice lacking the low density lipoprotein receptor.
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The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia
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Heparan sulfate proteoglycans are concentrated on the sinusoidal plasmalemmal domain and in intracellular organelles of hepatocytes.
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Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver
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Apolipoprotein E2 Reduces the Low Density Lipoprotein Level in Transgenic Mice by Impairing Lipoprotein Lipase-mediated Lipolysis of Triglyceride-rich Lipoproteins
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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.
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A comparison of the roles of the low density lipoprotein (LDL) receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor in chylomicron remnant removal in the mouse in vivo
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Relative roles of the LDL receptor, the LDL receptor-like protein, and hepatic lipase in chylomicron remnant removal by the liver.
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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.
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Enrichment of apolipoprotein B-48 in the LDL density class following in vivo inhibition of hepatic lipase
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Role of Heparan Sulfate Proteoglycans and the LDL Receptor‐Related Protein in Remnant Lipoprotein Metabolisma
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Novel members of the low density lipoprotein receptor superfamily and their potential roles in lipid metabolism
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Basic fibroblast growth factor (FGF-2) internalization through the heparan sulfate proteoglycans-mediated pathway: an ultrastructural approach.
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Lipases and lecithin: cholesterol acyltransferase in the control of lipoprotein metabolism
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The human asialoglycoprotein receptor is a possible binding site for low-density lipoproteins and chylomicron remnants
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Cellular binding site and membrane binding proteins for triglyceride-rich lipoproteins in human monocyte-macrophages and THP-1 monocytic cells.
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Chinese Hamster Ovary Cells Expressing a Cell Surface-anchored Form of Hepatic Lipase
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Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene.
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Lipoprotein lipase-mediated uptake of lipoprotein in human fibroblasts: evidence for an LDL receptor-independent internalization pathway
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Secretion-recapture process of apolipoprotein E in hepatic uptake of chylomicron remnants in transgenic mice.
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Free fatty acids activate a high-affinity saturable pathway for degradation of low-density lipoproteins in fibroblasts from a subject homozygous for familial hypercholesterolemia
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Hepatic lipase treatment of chylomicron remnants increases exposure of apolipoprotein E.
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Chylomicron remnant uptake is regulated by the expression and function of heparan sulfate proteoglycan in hepatocytes
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Adenovirus-Mediated Gene Transfer of Human Lipoprotein Lipase Ameliorates the Hyperlipidemias Associated with Apolipoprotein E and LDL Receptor Deficiencies in Mice
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Genetic Defects in Lipoprotein Metabolism
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Mechanism of Activation and Functional Significance of the Lipolysis-Stimulated Receptor. Evidence for a Role as Chylomicron Remnant Receptor
Mann, C. J., Khallou‐Laschet, J., Chevreuil, O., Troussard, A. A., Guermani, L. M., Launay, K., Delplanque, B., Yen, F. T., & Bihain, B. E. (1995) · Biochemistry · doi:10.1021/bi00033a014 · Cited by 43 · see citing works
Transgenic mice expressing human lipoprotein lipase driven by the mouse metallothionein promoter. A phenotype associated with increased perinatal mortality and reduced plasma very low density lipoprotein of normal size.
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Resistance of a very low density lipoprotein subpopulation from familial dysbetalipoproteinemia to in vitro lipolytic conversion to the low density lipoprotein density fraction.
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Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.
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Uptake of hypertriglyceridemic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans
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Exogenous receptor-associated protein binds to two distinct sites on human fibroblasts but does not bind to the glycosaminoglycan residues of heparan sulfate proteoglycans.
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Differences in the Mechanisms of Uptake and Endocytosis of Small and Large Chylomicron Remnants by Rat Liver
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Recognition of lactoferrin and aminopeptidase M-modified lactoferrin by the liver: involvement of proteoglycans and the remnant receptor
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Genetic Factors Precipitating Type III Hyperlipoproteinemia in Hypolipidemic Transgenic Mice Expressing Human Apolipoprotein E2
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Lipoprotein lipase in liver. Release by heparin and immunocytochemical localization
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Uptake and degradation of rat and human very low density (remnant) apolipoprotein by parenchymal and non-parenchymal rat liver cells
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Hepatic lipase function and the accumulation of β-very-low-density lipoproteins in the plasma of cholesterol-fed rabbits
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Inhibitory Effect on the Lipolysis-stimulated Receptor of the 39-kDa Receptor-associated Protein
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Genetic Defects in Lipoprotein Metabolism
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The Postprandial State: Mechanisms of Glucose Intolerance
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In vivo removal of beta-VLDL, chylomicron remnants, and alpha 2-macroglobulin in the rat.
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Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lysl46→Gln) are inefficiently converted to cholesterol-rich lipoproteins
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Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
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Dyslipidemia in obesity: Mechanisms and potential targets
Klop, B., Elte, J., & Cabezas, M. (2013) · Nutrients · doi:10.3390/nu5041218 · Cited by 1,665 · see citing works
Heparan sulphate proteoglycans fine-tune mammalian physiology
Bishop, J. R., Schuksz, M., & Esko, J. D. (2007) · Nature · doi:10.1038/nature05817 · Cited by 1,631 · see citing works
Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms
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Diabetic dyslipidaemia: from basic research to clinical practice*
Taskinen, M.-R. (2003) · Diabetologia · doi:10.1007/s00125-003-1111-y · Cited by 888 · see citing works
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
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Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Mahley, R. W. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1427-y · Cited by 837 · see citing works
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Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism
Mahley, R. W. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307023 · Cited by 516 · see citing works
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Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus
Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524 · see citing works
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Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes
Mahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447 · see citing works
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Apolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412 · see citing works
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Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial
Gaudet, D., Méthot, J., Déry, S., Brisson, D., Essiembre, C., Tremblay, G., Tremblay, K., de Wal, J., Twisk, J., van den Bulk, N., et al. (2013) · Gene Therapy · doi:10.1038/gt.2012.43 · Cited by 404 · see citing works
Apolipoprotein E isoforms and lipoprotein metabolism
Phillips, M. C. (2014) · IUBMB Life · doi:10.1002/iub.1314 · Cited by 328 · see citing works
Internalization of Exosomes through Receptor-Mediated Endocytosis
Gonda, A., Kabagwira, J., Senthil, G. N., & Wall, N. R. (2019) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0891 · Cited by 296 · see citing works
Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors in Sporadic Alzheimer’s Disease
Harris, S. A., & Harris, E. A. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142853 · Cited by 279 · see citing works
Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance
Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · see citing works
New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism
Ginsberg, H. N. (2002) · Circulation · doi:10.1161/01.cir.0000035280.64322.31 · Cited by 255 · see citing works
Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans
Reyes-Soffer, G., Pavlyha, M., Ngai, C., Thomas, T., Holleran, S., Ramakrishnan, R., Karmally, W., Nandakumar, R., Fontanez, N., Obunike, J., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.025253 · Cited by 240 · see citing works
Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk
Chapman, M. J., Redfern, J. S., McGovern, M. E., & Giral, P. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.01.008 · Cited by 227 · see citing works
Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
MacArthur, J. M., Bishop, J. R., Stanford, K. I., Wang, L., Bensadoun, A., Witztum, J. L., & Esko, J. D. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29154 · Cited by 216 · see citing works
Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210 · see citing works
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Lopera, F., Marino, C., Chandrahas, A. S., O’Hare, M., Villalba-Moreno, N. D., Aguillon, D., Baena, A., Sanchez, J. S., Vila-Castelar, C., Ramirez Gomez, L., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02318-3 · Cited by 192 · see citing works
Postprandial hypertriglyceridemia as a coronary risk factor
Borén, J., Matikainen, N., Adiels, M., & Taskinen, M.-R. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.01.015 · Cited by 182 · see citing works
Apolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · see citing works
<i><scp>APOE</scp></i>‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165 · see citing works
Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing
Mahley, R. W., & Huang, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30889 · Cited by 159 · see citing works
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Lipid nanoparticles for short interfering RNA delivery
Leung, A. K. K., Tam, Y. Y. C., & Cullis, P. R. (2014) · Advances in genetics · doi:10.1016/b978-0-12-800148-6.00004-3 · Cited by 158 · see citing works
Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation
Heeren, J., Grewal, T., Laatsch, A., Becker, N., Rinninger, F., Rye, K.-A., & Beisiegel, U. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409324200 · Cited by 139 · see citing works
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030176 · Cited by 129 · see citing works
Reactivity of Apolipoprotein E4 and Amyloid β Peptide
Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., Huang, Y., & Mahley, R. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m506646200 · Cited by 127 · see citing works
Adipose tissue gene expression of factors related to lipid processing in obesity
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Authors: Mahley, R. W., & Ji, Z.-S.
Affiliations: University of California, San Francisco (US)
Corresponding author: Mahley, Robert W.
ORCID: Mahley, Robert W.
Venue: Journal of Lipid Research
Publisher: Elsevier BV
Published: 1999-01
Volume: 40
Issue: 1
Pages: 1-16
ISSN: 0022-2275 (ISSN-L)
DOI: 10.1016/s0022-2275(20)33334-4
OpenAlex: W2150436995
Cited by: 693
References: 132
Citations by year: 2026: 16 · 2025: 15 · 2024: 9 · 2023: 16 · 2022: 15 · 2021: 20 · 2020: 15 · 2019: 17 · 2018: 20 · 2017: 12 · 2016: 15 · 2015: 22 · 2014: 27 · 2013: 26 · 2012: 23
FWCI: 34.41
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7914 d)
Locations: Journal of Lipid Research (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (5p01hl047660-10)
National Heart, Lung, and Blood Institute (HL-41633, P01HL041633, HL-47660)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords: heparan sulfate proteoglycans, apolipoprotein E, space of Disse, lipoprotein lipase, hepatic lipase, LDL receptor, LDL receptor-related protein, endocytosis, hepatocytes, intestinal lipoproteins
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Biological Transport, Active, Cell Membrane, Chylomicrons, Endocytosis, Humans, Hyperlipoproteinemia Type III, Lipase, Lipoprotein Lipase, Lipoproteins, Liver, Receptors, Immunologic, Receptors, LDL, Heparan Sulfate Proteoglycans, Low Density Lipoprotein Receptor-Related Protein-1

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Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

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