title: A monogalactosylated cholesterol derivative that specifically induces uptake of LDL by the liver.
abstract: 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.
authors.affiliation: Division of Biopharmaceutics, University of Leiden, The Netherlands.
authors.forename: M K
authors.initials: MK
authors.lastname: Bijsterbosch
authors.forename: H F
authors.initials: HF
authors.lastname: Bakkeren
authors.forename: H J
authors.initials: HJ
authors.lastname: Kempen
authors.forename: H C
authors.initials: HC
authors.lastname: Roelen
authors.forename: J H
authors.initials: JH
authors.lastname: van Boom
authors.forename: T J
authors.initials: TJ
authors.lastname: van Berkel
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002788:Cholesterol Esters / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology*
chemical_list: D001053:Apolipoproteins; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D013873:Thionucleotides; C039707:galactose receptor; C077516:O-(11-(5-cholesten-3-yloxy)3,6,9-trioxaundecyl) O-(2-(galactopyranosyloxy)ethyl) phosphorothioate; C042924:N-(tris((beta-galactopyranosyloxy)methyl)methyl)-N(alpha)-(4-(5-cholesten-3 beta-yloxy)succinyl)glycinamide; D002784:Cholesterol