This Article Full Text Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biessen, E. A.L. Articles by van Berkel, T. J.C. Search for Related Content PubMed PubMed Citation Articles by Biessen, E. A.L. Articles by van Berkel, T. J.C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1552-1558.)
© 1996 American Heart Association, Inc.

Articles

Induction of Hepatic Uptake of Lipoprotein(a) by Cholesterol-Derivatized Cluster Galactosides

Erik A.L. Biessen; Helene Vietsch; Theo J.C. van Berkel

the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.

Correspondence to Dr E.A.L. Biessen, Division of Biopharmaceutics, Sylvius Laboratories, University of Leiden, PO Box 9503, 2300 RA Leiden, Netherlands.

We have previously developed triantennary galactosides [TG(4Å)C and TG(20Å)C] that lower cholesterol levels by inducing liver uptake of lipoproteins via galactose-recognizing hepatic receptors. In this study, we have investigated whether this strategy could also be applied to reduce elevated serum levels of the atherogenic lipoprotein(a) [Lp(a)]. Both TG(4Å)C and TG(20Å)C could be incorporated into Lp(a). Incorporation of these glycolipids induced a rapid clearance of Lp(a). Concomitantly, the hepatic uptake of ¹²⁵I-Lp(a) was enhanced from 4±1% to 80±4% of the injected dose for TG(4Å)C (P<.0001) and to 17±4% of the injected dose for TG(20Å)C (P<.006). TG(4Å)C was apparently more effective in accelerating the serum decay of ¹²⁵I-Lp(a), which may be caused by the higher hydrophobicity of this glycolipid relative to TG(20Å)C. The TG(4Å)C- and TG(20Å)C-induced stimulation of the serum decay and liver uptake of ¹²⁵I-Lp(a) could be significantly inhibited (>85%) by preinjection of N-acetyl-galactosamine (150 mg), indicating that galactose-recognizing receptors are involved in the liver uptake of the glycolipid/Lp(a) complexes. The TG(4Å)C-induced liver uptake of ¹²⁵I-Lp(a) could be ascribed mainly to Kupffer cells (76±7%), whereas the parenchymal liver cell was the major site for liver uptake of TG(20Å)C-laden ¹²⁵I-Lp(a) (55±12%). In conclusion, both TG(4Å)C and TG(20Å)C stimulate the catabolism of ¹²⁵I-Lp(a) by enhancing hepatic uptake. Because endocytosis of the substrate via galactose-recognizing receptors on Kupffer and parenchymal liver cells is followed by lysosomal degradation, we anticipate that both approaches for Lp(a) targeting may prove valuable as therapeutic modalities for lowering atherogenic levels of Lp(a).

Key Words: apolipoprotein(a) • glycolipids • atherosclerosis • lipoproteins • hypercholesterolemia

This article has been cited by other articles:

				P. C. N. Rensen, L. A. J. M. Sliedregt, M. Ferns, E. Kieviet, S. M. W. van Rossenberg, S. H. van Leeuwen, T. J. C. van Berkel, and E. A. L. Biessen Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytes in Vitro and in Vivo J. Biol. Chem., September 28, 2001; 276(40): 37577 - 37584. [Abstract] [Full Text] [PDF]