A monogalactosylated cholesterol derivative that specifically induces uptake of LDL by the liver

We described earlier the effect of tris-gal-chol (a triantennary galactose structure coupled to cholesterol) on the fate of low density lipoprotein (LDL) and high density lipoprotein (HDL). Tris-gal-chol-loaded LDL and HDL are both efficiently cleared from blood by hepatic galactose-specific receptors. Thus, tris-gal-chol combines a beneficial LDL-reducing effect with an equally effective but undesirable HDL-lowering effect. We recently synthesized a cholesterol derivative with a single terminal galactose residue, denoted mono-gal-chol. In the present study we show that this compound, which incorporates readily into both LDL and HDL, induces rapid association of LDL and HDL to the liver. The mono-gal-chol-stimulated hepatic association of HDL, however, was about fivefold lower than that of LDL. In the liver, Kupffer cells were mainly (90%) responsible for the liver uptake of mono-gal-chol-loaded LDL, whereas the complex of mono-gal-chol with HDL was predominantly (95%) taken up by parenchymal cells. Uptake by both cell types proceeded via galactose-specific receptors and was followed by degradation of the apolipoproteins in the lysosomes. Thus, compared with tris-gal-chol, mono-gal-chol is equally effective in the induction of galactose-specific uptake of LDL by Kupffer cells. However, the galactose-specific receptor on parenchymal cells recognizes mono-gal-chol-loaded HDL less efficiently than tris-gal-chol-containing HDL. These results indicate that mono-gal-chol might be used to specifically lower LDL levels in patients with a high LDL cholesterol level.