Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice
Open accessAbstract
Objective—: Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear. Approach and Results—: Triglyceride-rich lipoprotein clearance was measured in AlbCre + Ndst1 f/f , Ldlr −/− , and AlbCre + Lrp1 f/f mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors ( AlbCre + Ndst1 f/f Lrp1 f/f Ldlr −/− ) displayed dramatic hyperlipidemia (870±270 mg triglyceride/dL; 1300±350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈20–40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈40–60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet. Conclusions—: These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.
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All chylomicron remnants and variable amounts of VLDL remnants undergo direct hepatic clearance mainly involving the LDL receptor, although studies in mice suggest putative roles for LDL receptor-related protein 1 and heparan sulphate proteoglycans, particularly syndecan 1.
“As stated above, all chylomicron remnants and variable amounts of VLDL remnants undergo direct hepatic clearance (Figures 2 and 4), mainly involving the LDL receptor, although studies in mice suggest putative roles for LDL receptor-related protein 1 and heparan sulphate proteoglycans (particularly syndecan 1).69,70”
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Cites
Nordestgaard, B. G., Benn, M., Schnohr, P., & Tybjærg-Hansen, A. (2007) · JAMA · doi:10.1001/jama.298.3.299 · Cited by 2,058 · see citing works
Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women
Bansal, S., Buring, J. E., Rifai, N., Mora, S., Sacks, F. M., & Ridker, P. M. (2007) · JAMA · doi:10.1001/jama.298.3.309 · Cited by 1,619 · see citing works
Hypertriglyceridemia: its etiology, effects and treatment
Yuan, G., Al-Shali, K. Z., & Hegele, R. A. (2007) · Canadian Medical Association Journal · doi:10.1503/cmaj.060963 · Cited by 624 · see citing works
Rohlmann, A., Gotthardt, M., Hammer, R. E., & Herz, J. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1240 · Cited by 455 · see citing works
Fujino, T., Asaba, H., Kang, M., Ikeda, Y., Sone, H., Takada, S., Kim, D.-H., Ioka, R. X., Ono, M., Tomoyori, H., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0133792100 · Cited by 399 · see citing works
Heparan sulfate proteoglycan as a plasma membrane carrier
Belting, M. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00031-8 · Cited by 312 · see citing works
May, P., Woldt, E., Matz, R. L., & Boucher, P. (2007) · Annals of Medicine · doi:10.1080/07853890701214881 · Cited by 267 · see citing works
Kita, T., Goldstein, J. L., Brown, M. S., Watanabe, Y., Hornick, C. A., & Havel, R. J. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.11.3623 · Cited by 259 · see citing works
Williams, K. J., Fless, G. M., Petrie, K. A., Snyder, M. L., Brocia, R. W., & Swenson, T. L. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)42208-9 · Cited by 257 · see citing works
Ji, Z. S., Brecht, W. J., Miranda, R. D., Hussain, M. M., Innerarity, T. L., & Mahley, R. W. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82186-x · Cited by 240 · see citing works
Stanford, K. I., Bishop, J. R., Foley, E. M., Gonzales, J. C., Niesman, I. R., Witztum, J. L., & Esko, J. D. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38251 · Cited by 226 · see citing works
Self-citationMacArthur, 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
Self-citationLawrence, R., Olson, S. K., Steele, R. E., Wang, L., Warrior, R., Cummings, R. D., & Esko, J. D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804288200 · Cited by 195 · see citing works
Self-citationRensen, P. C. N., Herijgers, N., Netscher, M. H., Meskers, S. C. J., Eck, M. V., & van Berkel, T. J. C. (1997) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37190-x · Cited by 165 · see citing works
Mahley, R. W., & Huang, Y. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30889 · Cited by 159 · see citing works
Ji, Z.-S., Dichek, H. L., Miranda, R. D., & Mahley, R. W. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.50.31285 · Cited by 156 · see citing works
Rubinsztein, D. C., Cohen, J. C., Berger, G. M. B., van der Westhuyzen, D. R., Coetzee, G. A., & Gevers, W. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114839 · Cited by 149 · see citing works
Lawrence, R., Lu, H., ROSENBERG, R. D., Esko, J. D., & Zhang, L. (2008) · Nature Methods · doi:10.1038/nmeth0408-291 · Cited by 146 · see citing works
Self-citationCell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism
Williams, K. J., & Fuki, I. V. (1997) · Current Opinion in Lipidology · doi:10.1097/00041433-199710000-00003 · Cited by 135 · see citing works
Role of the Low Density Lipoprotein (LDL) Receptor Pathway in the Metabolism of Chylomicron Remnants
Ishibashi, S., Perrey, S., Chen, Z., Osuga, J.-I., Shimada, M., Ohashi, K., Harada, K., Yazaki, Y., & Yamada, N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.37.22422 · Cited by 129 · see citing works
Stalenhoef, A. F., & de Graaf, J. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328304b63c · Cited by 121 · see citing works
Ji, Z. S., Sanan, D. A., & Mahley, R. W. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39892-8 · Cited by 106 · see citing works
[7] Density gradient ultracentrifugation of serum lipoproteins in a swinging bucket rotor
Kelley, J., & Kruski, A. W. (1986) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(86)28067-2 · Cited by 105 · see citing works
Goudriaan, J. R., Santo, S. M. S. E., Voshol, P. J., Teusink, B., van Dijk, K. W., van Vlijmen, B. J. M., Romijn, J. A., Havekes, L. M., & Rensen, P. C. N. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m400009-jlr200 · Cited by 100 · see citing works
Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo
Eck, M. V., Hoekstra, M., Out, R., Bos, I. S. T., Kruijt, J. K., Hildebrand, R. B., & van Berkel, T. J. C. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m700355-jlr200 · Cited by 97 · see citing works
Lipolysis Stimulated Lipoprotein Receptor
Yen, F. T., Roitel, O., Bonnard, L., Notet, V., Pratte, D., Stenger, C., Magueur, E., & Bihain, B. E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801027200 · Cited by 93 · see citing works
Recent insights into factors affecting remnant lipoprotein uptake
Williams, K. J., & Chen, K. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328338cabc · Cited by 91 · see citing works
Heparan Sulfate 2-O-Sulfotransferase Is Required for Triglyceride-rich Lipoprotein Clearance
Stanford, K. I., Wang, L., Castagnola, J., Song, D., Bishop, J. R., Brown, J. R., Lawrence, R., Bai, X., Habuchi, H., Tanaka, M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.063701 · Cited by 84 · see citing works
Self-citationWilsie, L. C., & Orlando, R. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208786200 · Cited by 81 · see citing works
Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans
Gonzales, J. C., Gordts, P. L. S. M., Foley, E. M., & Esko, J. D. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67398 · Cited by 79 · see citing works
Self-citationde Faria, E. C., Fong, L. G., Komaromy, M. C., & Cooper, A. D. (1996) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)37648-3 · Cited by 75 · see citing works
Mortimer, B., Beveridge, D. J., Martins, I. J., & Redgrave, T. G. (1995) · PubMed · doi:10.1074/jbc.270.48.28767 · Cited by 74 · see citing works
Elson‐Schwab, L., Garner, O. B., Schuksz, M., Crawford, B. E., Esko, J. D., & Tor, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700463200 · Cited by 73 · see citing works
Self-citationMann, W. A., Meyer, N., Weber, W. T., Meyer, S., Greten, H., & Beisiegel†, U. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39885-0 · Cited by 47 · see citing works
Hepatic Heparan Sulfate Proteoglycans and Endocytic Clearance of Triglyceride-Rich Lipoproteins
Foley, E. M., & Esko, J. D. (2010) · Progress in molecular biology and translational science · doi:10.1016/s1877-1173(10)93010-x · Cited by 45 · see citing works
Self-citationMann, 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
Shedding of Syndecan–1 From Human Hepatocytes Alters Very Low Density Lipoprotein Clearance
Deng, Y., Foley, E. M., Gonzales, J. C., Gordts, P. L. S. M., Li, Y., & Esko, J. D. (2011) · Hepatology · doi:10.1002/hep.24626 · Cited by 43 · see citing works
Self-citationSanto, S. M. S. E., Pires, N. M., Boesten, L. S. M., Gerritsen, G., Bovenschen, N., van Dijk, K. W., Jukema, J. W., Princen, H. M. G., Bensadoun, A., Li, W., et al. (2004) · Blood · doi:10.1182/blood-2003-11-4051 · Cited by 43 · see citing works
Windler, E. E. T., Greeve, J. C., Robenek, H., Rinninger, F., Greten, H., & Jäckle, S. (1996) · Hepatology · doi:10.1053/jhep.1996.v24.pm0008690403 · Cited by 35 · see citing works
Santo, S. M. S. E., Rensen, P. C. N., Goudriaan, J. R., Bensadoun, A., Bovenschen, N., Voshol, P. J., Havekes, L. M., & van Vlijmen, B. J. M. (2005) · Journal of Lipid Research · doi:10.1194/jlr.c500007-jlr200 · Cited by 31 · see citing works
Mann, W. A., Lohse, P., Gregg, R. E., Ronan, R., Hoeg, J. M., Zech, L. A., & Brewer, H. B. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118096 · Cited by 28 · see citing works
Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis
Waern, I., Karlsson, I., Thorpe, M., Schlenner, S., Feyerabend, T. B., Rodewald, H.-R., Åbrink, M., Hellman, L., Pejler, G., & Wernersson, S. (2012) · Biological Chemistry · doi:10.1515/hsz-2012-0189 · Cited by 27 · see citing works
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Research works printed but not linked: 5
- [1]MacArthur JM Bishop JR Wang L Stanford KI 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 17200715 PMC1716206
- [2]Kelley JL Kruski AW Density gradient ultracentrifugation of serum lipoproteins in a swinging bucket rotor Methods Enzymol 1986 128 170 181 3724501
- [4]Deng Y Foley EM Gonzales JC Gordts PL Li Y Esko JD Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance Hepatology 55 277 286 21898481 PMC3245353
- [5]Lawrence R Olson SK Steele RE Wang L Warrior R Cummings RD Esko JD Evolutionary differences in glycosaminoglycan fine structure detected by quantitative glycan reductive isotope labeling J Biol Chem 2008 283 33674 33684 18818196 PMC2586254
- [6]Stanford KI Bishop JR Foley EM Gonzales JC Niesman IR Witztum JL Esko JD Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice J Clin Invest 2009 119 3236 3245 19805913 PMC2769193
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ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors
Gordts, P. L. S. M., Nock, R., Son, N.-H., Ramms, B., Lew, I., Gonzales, J. C., Thacker, B. E., Basu, D., Lee, R. G., Mullick, A. E., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86610 · Cited by 274 · see citing works
Self-citationAdam, R. C., Mintah, I. J., Alexa-Braun, C. A., Shihanian, L. M., Lee, J. S., Banerjee, P., Hamon, S. C., Kim, H. I., Cohen, J. C., Hobbs, H. H., et al. (2020) · Journal of Lipid Research · doi:10.1194/jlr.ra120000888 · Cited by 208 · see citing works
Human genetic disorders and knockout mice deficient in glycosaminoglycan
Mizumoto, S., Yamada, S., & Sugahara, K. (2014) · BioMed Research International · doi:10.1155/2014/495764 · Cited by 54 · see citing works
- Authors
- Foley, E. M., Gordts, P. L. S. M., Stanford, K. I., Gonzales, J. C., Lawrence, R., Stoddard, N., & Esko, J. D.
- Affiliations
- Harvard University (US)
- From the Department of Cellular and Molecular Medicine (E.M.F., P.L.S.M.G., J.C.G., R.L., N.S., J.D.E.) and Biomedical Sciences Graduate Program (E.M.F., J.C.G., N.S., J.D.E.), University of California San Diego, La Jolla, CA; and Section on Integrative Physiology and Metabolism, Joslin Diabetes Research Center, Harvard University, Cambridge, MA (K.I.S.).
- Corresponding author
- Esko, Jeffrey D.
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2013-09
- Volume
- 33
- Issue
- 9
- Pages
- 2065-2074
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC3821931
- OpenAlex
- W2004873841
- Cited by
- 77
- References
- 42
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 10 · 2017: 1 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 2
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (T32CA067754)
- National Institute of General Medical Sciences (R01GM033063, R37GM033063, GM-33063)
- 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, syndecan-1, LDL receptor, triglyceride-rich lipoproteins, chylomicron remnants, hyperlipidemia, postprandial triglycerides, high-fat diet, NDST1
- MeSH terms
- Animals, Cells, Cultured, Cholesterol, Dietary, Hyperlipidemias, Liver, Mice, Inbred C57BL, Particle Size, Receptors, LDL, Time Factors, Triglycerides, Sulfotransferases, Mice, Knockout, Dietary Sucrose, Postprandial Period, Heparan Sulfate Proteoglycans, Hepatocytes, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Chylomicron Remnants, Diet, High-Fat
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