Original Article

Chylomicron remnant uptake is regulated by the expression and function of heparan sulfate proteoglycan in hepatocytes

Correspondence to: Trevor G. Redgrave.

Chylomicron remnants transport cholesterol from the intestine, and are removed from the circulation principally by the liver. While hepatic receptors, including the low density lipoprotein (LDL) receptor account for endocytosis, heparan sulfate proteoglycans (HSPG) participate in the initial binding of remnants to liver cells. To explore the interactions between HSPG and endocytosis of remnants, in the present study the expression of HSPG was inhibited in HepG2 cells transfected by a synthetic antisense oligodeoxynucleotide SYN5. Immunofluorescent staining by a monoclonal anti-syndecan antibody showed significant reduction in the expression of syndecan in SYN5-treated cells compared with control cells. Remnant binding decreased by about 50–70% in SYN5-transfected cells. Monoclonal antibodies to either heparan sulphate or the LDL receptor decreased binding by about 60–65%. The glycosylation inhibitor ß-nitrophenyl-xylopyranoside inhibited remnant uptake by 25%, whereas 4-nitrophenyl-ß-D-galactopyranoside had no effect on remnant binding. Heparinase completely abolished binding at appropriate concentrations. Heparitinase was less effective than heparinase in inhibiting remnant binding. Suramin completely abolished the remnant binding. Poly-arginine, poly-lysine, and protamine all reduced remnant uptake by the cells, as did polybrene, a synthetic polycation, suggesting a role of cation–anion interactions in remnant binding. Brefeldin A, colchicine, and monensin caused the fluorescence associated with remnants to persist within the cells, confirming that blockers of tubulovesicular processes and Golgi function inhibit the intracellular transport and degradation of the remnants.

Our results show that remnant binding to liver cells depends on the LDL receptor, on the expression of HSPG core proteins, and on the functionality of heparan sulfate in HSPG.—Zeng, B-J., B-C. Mortimer, I. J. Martins, U. Seydel, and T. G. Redgrave. Chylomicron remnant uptake is regulated by the expression and function of heparan sulfate proteoglycan in hepatocytes. J. Lipid Res. 1998. 39: 845–860.

Supplementary key words: antisense, antibody, competitor, inhibitor, receptor, blocker, metabolism, lipoprotein, glycosaminoglycan, confocal microscope

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Hu, C. C. van der Hoogt, S. M. S. Espirito Santo, R. Out, K. E. Kypreos, B. J. M. van Vlijmen, T. J. C. Van Berkel, J. A. Romijn, L. M. Havekes, K. W. van Dijk, et al. The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI J. Lipid Res., July 1, 2008; 49(7): 1553 - 1561. [Abstract] [Full Text] [PDF]

				S. Gingis-Velitski, A. Zetser, V. Kaplan, O. Ben-Zaken, E. Cohen, F. Levy-Adam, Y. Bashenko, M. Y. Flugelman, I. Vlodavsky, and N. Ilan Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans J. Biol. Chem., October 15, 2004; 279(42): 44084 - 44092. [Abstract] [Full Text] [PDF]

				L. C. Wilsie and R. A. Orlando The Low Density Lipoprotein Receptor-related Protein Complexes with Cell Surface Heparan Sulfate Proteoglycans to Regulate Proteoglycan-mediated Lipoprotein Catabolism J. Biol. Chem., April 25, 2003; 278(18): 15758 - 15764. [Abstract] [Full Text] [PDF]

				H. W. Harris and F. B. Kasravi Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes Innate Immunity, February 1, 2003; 9(1): 45 - 50. [Abstract] [PDF]

				U. Olsson, A.-C. Egnell, M. R. Lee, G. O. Lunden, M. Lorentzon, M. Salmivirta, G. Bondjers, and G. Camejo Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance Diabetes, September 1, 2001; 50(9): 2126 - 2132. [Abstract] [Full Text] [PDF]

				G. Datta, D. W. Garber, B. H. Chung, M. Chaddha, N. Dashti, W. A. Bradley, S. H. Gianturco, and G. M. Anantharamaiah Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo J. Lipid Res., June 1, 2001; 42(6): 959 - 966. [Abstract] [Full Text]

				R. W. Mahley and Z.-S. Ji Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E J. Lipid Res., January 1, 1999; 40(1): 1 - 16. [Abstract] [Full Text]