Ligand size is a major determinant of high-affinity binding of fucose- and galactose-exposing (lipo)proteins by the hepatic fucose receptor

Biessen, Erik A.L.; Bakkeren, H. F.; Beuting, D. M.; Kuiper, Johan; Berkel, Theo J.C. Van

doi:10.1042/bj2990291

Cited by 58 publications

(47 citation statements)

References 29 publications

(24 reference statements)

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“…It can be calculated that at an incorporation of 50% (w/w) of glycolipid, the glycoside occupies only a very restricted surface area (approximately 3 nm 2 ) (32). In this case, the conformational properties of the individual clusters of the Gal 3 -terminated glycolipid, which are of vital importance for high affinity recognition by the ASGPr, may be overruled by the high overall Gal density on the liposomal surface, which has been shown to lead to efficient uptake by the GPr on Kupffer cells (27). Apparently, the preferential uptake of liposomes provided with an equal concentration (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The freeze-dried glycolipids were dissolved in PBS at a final concentration of 25-50 g/l and stored at Ϫ80°C under argon before use. Their stability (which exceeded 12 months) was routinely checked by thin layer chromatography (n-butanol, n-propanol, 25% NH 4 In Vitro Binding to Hepatocytes-Hepatocytes were isolated from anesthetized rats or mice by perfusion of the liver with collagenase (type IV, 0.05%, w/v) for 10 min at 37°C according to the method of Seglen (47) as detailed earlier (27). The cells were Ն99% pure as judged by light microscopy, and their viabilities were Ն95% (rat) and Ն80% (mouse) as determined by 0.2% trypan blue exclusion.…”

Section: Animalsmentioning

confidence: 99%

“…In contrast, the GPr predominantly recognizes larger galactose-exposing particles (Ͼ15 nm) (26 -28), such as desialylated rat erythrocytes (29,30), low density lipoproteins that are lactosylated (26) or provided with mono-Gal-Chol (22,23) and Tris-Gal-Chol (31), and Tris-Gal-Chol-exposing liposomes (31). The affinity of glycosides for the GPr was shown to increase with particle size to reach a maximum at 15 nm (27). Furthermore, it has been shown that the GPr preferentially recognizes a high density of either fucose or galactose on either proteins (13,15) or particles (26,32).…”

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confidence: 99%

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Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo

Rensen

Sliedregt

Ferns

et al. 2001

Journal of Biological Chemistry

188

160

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The asialoglycoprotein receptor (ASGPr) on hepatocytes plays a role in the clearance of desialylated proteins from the serum. Although its sugar preference (N-acetylgalactosamine (GalNAc) > > galactose) and the effects of ligand valency (tetraantennary > triantennary > > diantennary > > monoantennary) and sugar spacing (20 Å > > 10 Å > > 4 Å) are well documented, the effect of particle size on recognition and uptake of ligands by the receptor is poorly defined. In the present study, we assessed the maximum ligand size that still allows effective processing by the ASGPr of mouse hepatocytes in vivo and in vitro. Hereto, we synthesized a novel glycolipid, which possesses a highly hydrophobic steroid moiety for stable incorporation into liposomes, and a triantennary GalNAc 3 -terminated cluster glycoside with a high nanomolar affinity (2 nM) for the ASGPr. Incorporation of the glycolipid into small (30 nm) [ 3 H]cholesteryl oleate-labeled long circulating liposomes (1-50%, w/w) caused a concentration-dependent increase in particle clearance that was liver-specific (reaching 85 ؎ 7% of the injected dose at 30 min after injection) and mediated by the ASGPr on hepatocytes, as shown by competition studies with asialoorosomucoid in vivo. By using glycolipid-laden liposomes of various sizes between 30 and 90 nm, it was demonstrated that particles with a diameter of >70 nm could no longer be recognized and processed by the ASGPr in vivo. This threshold size for effective uptake was not related to the physical barrier raised by the fenestrated sinusoidal endothelium, which shields hepatocytes from the circulation, because similar results were obtained by studying the uptake of liposomes on isolated mouse hepatocytes in vitro. From these data we conclude that in addition to the species, valency, and orientation of sugar residues, size is also an important determinant for effective recognition and processing of substrates by the ASGPr. Therefore, these data have important implications for the design of ASGPr-specific carriers that are aimed at hepatocyte-directed delivery of drugs and genes.The hepatic asialoglycoprotein receptor (ASGPr) 1 is a C-type (Ca 2ϩ -dependent) lectin that is expressed on the surface of hepatocytes (1) and plays a role in the clearance (endocytosis and lysosomal degradation) of desialylated proteins from the serum (2, 3) as has been shown for cellular fibronectin (4) and all IgA2 allotypes (5). The human functional receptor is a noncovalent heterotetramer composed of two homologous type II membrane polypeptides with 55% sequence identity, generally called HL-1 (hepatic lectin 1) and HL-2, at a 2:2 stoichiometry (6). The ASGPr binds glycoproteins with either nonreducing terminal ␤-D-galactose (Gal) or N-acetylgalactosamine (GalNAc) residues, at which the affinity for GalNAc is approximately 50-fold higher than for Gal (7-9). From studies using mice that are deficient in either the subunit HL-1 (10) or HL-2 (11), it is evident that both polypeptides are necessary for efficient clearance of asialoglyco...

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo

Rensen

Sliedregt

Ferns

et al. 2001

Journal of Biological Chemistry

188

160

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“…Galactose-derived ligands, which are recognized by the asialoglycoprotein receptor (ASGPr), can be used to specifically target hepatocytes (28). Certain galactose-containing ligands enable hepatocyte uptake and avoidance of Kupffer cells if properly displayed on the delivery vehicle (29,30).…”

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confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

615

624

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Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers

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“…The uptake ratio between the ASGPr and GPr is defined in a complex manner by the size of a targeting agent and the surface distribution and exposure of Gal ligands. As with the LRP route, the specificity of the ASGPr route is enhanced by suppressing Kupffer cells (Lehrman, Pizzo, et al, 1986;Bijsterbosch & Van Berkel, 1990;Biessen et al, 1994;Kuiper et al, 1994;Sliedregt et al, 1999). The specificity of the ASGPr route also is increased by blocking the expression of ASGPr on activated T cells (Park, Kim, & Cho, 2006).…”

Section: Discussionmentioning

confidence: 99%

Peptide-mediated targeting of hepatocytes via low density lipoprotein receptor-related protein (LRP)

et al. 2009

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Ligand size is a major determinant of high-affinity binding of fucose- and galactose-exposing (lipo)proteins by the hepatic fucose receptor

Cited by 58 publications

References 29 publications

Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo

Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytesin Vitro and in Vivo

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Peptide-mediated targeting of hepatocytes via low density lipoprotein receptor-related protein (LRP)

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