INDUCTION OF HEPATIC-UPTAKE OF LIPOPROTEIN(A) BY CHOLESTEROL-DERIVATIZED CLUSTER GALACTOSIDES

We have previously developed triantennary galactosides [TG(4 Angstrom) C and TG(20 Angstrom)C] that lower cholesterol levels by inducing live r uptake of lipoproteins via galactose-recognizing hepatic receptors. In this study, we have investigated whether this strategy could also b e applied to reduce elevated serum levels of the atherogenic lipoprote in(a) [Lp(a)]. Both TG(4 Angstrom)C and TG(20 Angstrom)C could be inco rporated into Lp(a). Incorporation of these glycolipids induced a rapi d clearance of Lp(a). Concomitantly, the hepatic uptake of I-125-Lp(a) was enhanced from 4 +/- 1% to 80 +/- 4% of the injected dose for TG(4 Angstrom)C (P < .0001) and to 17 +/- 4% of the injected dose for TG(2 0 Angstrom)C (P < .006). TG(4 Angstrom)C was apparently more effective in accelerating the serum decay of I-125-Lp(a), which may be caused b y the higher hydrophobicity of this glycolipid relative to TG(20 Angst rom)C. The TG(4 Angstrom)C- and TG(20 Angstrom)C-induced stimulation o f the serum decay and liver uptake of I-125-Lp(a) could be significant ly 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(4 Angstrom)C-in duced liver uptake of I-125-Lp(a) could be ascribed mainly to Kupffer cells (76 +/- 7%), whereas the parenchymal liver cell was the major si te for liver uptake of TG(20 Angstrom)C-laden I-125-Lp(a) (55 +/- 12%) . In conclusion, both TG(4 Angstrom)C and TG(20 Angstrom)C stimulate t he catabolism of I-125-Lp(a) by enhancing hepatic uptake. Because endo cytosis of the substrate via galactose-recognizing receptors on Kupffe r and parenchymal liver cells is followed by lysosomal degradation, we anticipate that both approaches for Lp(a) targeting may prove valuabl e as therapeutic modalities for lowering atherogenic levels of Lp(a).