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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:169.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Stimulation of Liver-Directed Cholesterol Flux in Mice by Novel N-Acetylgalactosamine–Terminated Glycolipids With High Affinity for the Asialoglycoprotein Receptor

Patrick C.N. Rensen; Leo A.J.M. Sliedregt; Peter J. van Santbrink; Michiel Ferns; Hendrik N.J. Schifferstein; Steven H. van Leeuwen; John H.M. Souverijn; Theo J.C. van Berkel; Erik A.L. Biessen

From the Division of Biopharmaceutics (P.C.N.R., L.A.J.M.S., P.J.v.S., M.F., S.H.v.L., T.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, University of Leiden, Gorlaeus Laboratory, Leiden; the Department of Industrial Design (H.N.J.S.), Delft University of Technology, Delft; Central Clinical Chemical Laboratory of the Leiden University Medical Center (J.H.M.S.), Leiden; and the Department of General Internal Medicine (P.C.N.R. current address), Leiden University Medical Center, Leiden, The Netherlands.

Correspondence to Patrick C.N. Rensen, Leiden University Medical Center, Department of Endocrinology and Metabolism, C4-R81, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail P.C.N.Rensen{at}lumc.nl

Objective— Interventions that promote liver-directed cholesterol flux can suppress atherosclerosis, as demonstrated for scavenger receptor-BI overexpression in hypercholesterolemic mice. In analogy, we speculate that increasing lipoprotein flux to the liver via the asialoglycoprotein receptor (ASGPr) may be of therapeutic value in hypercholesterolemia.

Methods and Results— A bifunctional glycolipid (LCO-Tyr-GalNAc₃) with a high-nanomolar affinity for the ASGPr (inhibition constant 2.1±0.2 nmol/L) was synthesized that showed rapid association with lipoproteins on incubation with serum. Prior incubation of LCO-Tyr-GalNAc₃ with radiolabeled low-density lipoprotein or high-density lipoprotein (0.5 µg/µg of protein) resulted in a dramatic induction of the liver uptake of these lipoproteins when injected intravenously into mice (70±3% and 78±1%, respectively, of the injected dose at 10 minutes of low-density lipoprotein and high-density lipoprotein), as mediated by the ASGPr on hepatocytes. Intravenously injected LCO-Tyr-GalNAc₃ quantitatively incorporated into serum lipoproteins and evoked a strong and persistent (48 hour) cholesterol-lowering effect in normolipidemic mice (37±2% at 6 hours) and hyperlipidemic apoE^–/– mice (32±2% at 6 hours). The glycolipid was also effective on subcutaneous administration.

Conclusions— LCO-Tyr-GalNAc₃ is very effective in promoting cholesterol uptake by hepatocytes and, thus, may be a promising alternative for the treatment of those hyperlipidemic patients who do not respond sufficiently to conventional cholesterol-lowering therapies.

A bifunctional glycolipid with a high affinity for the asialoglycoprotein receptor on hepatocytes dramatically induced the hepatic uptake of lipoproteins and evoked strong and persistent cholesterol-lowering effects in mice. This glycolipid may be of added value in the treatment of patients who do not respond to conventional cholesterol-lowering therapies.

Key Words: cholesterol-lowering drugs • hyperlipoproteinemia • lipoproteins • receptors • transgenic models