Recognition of lactoferrin and aminopeptidase M-modified lactoferrin by the liver: involvement of the remnant receptor
Ziere, G.J.; Kruijt, J.K.; Bijsterbosch, M.K.; Berkel, T.J.
Zeitschrift für Gastroenterologie 34(Suppl 3): 118-121
1996
ISSN/ISBN: 0044-2771 PMID: 8767485 Document Number: 455607
Lactoferrin inhibits the hepatic uptake of lipoprotein remnants, and we showed earlier that arginine residues of lactoferrin are involved. In this study, lactoferrin was treated with aminopeptidase-M (APM), which resulted in removal of 14 N-terminal amino acids, including 4 clustered arginines at positions 2-5 (APM-lactoferrin). After i.v. injection into rats, 125I-APM-lactoferrin was cleared within 10 min by the liver parenchymal cells (74.7% of the dose). Binding of APM-lactoferrin to isolated parenchymal liver cells was saturable with a Kd of 186 nM (750.000 sites/cell). This is in striking contrast to the binding of lactoferrin (Kd 10 microM; 20 x 10(6) sites/cell). Preinjection of rats with 20 mg of APM-lactoferrin/kg body weight reduced the liver association of beta-VLDL by 50%, whereas lactoferrin had no effect at this dose. With isolated parenchymal liver cells, APM-lactoferrin was a more effective competitor for beta-VLDL binding than native lactoferrin (50% inhibition at 0.5 mg/ml vs. 8.0 mg/ml). We conclude that the 4-arginine cluster of lactoferrin at position 2-5 involved in the massive association of lactoferrin with the parenchymal liver cell, but is not essential for the inhibition of the lipoprotein remnant uptake. The Arg/Lys sequence at position 25-30, which resembles the binding site of apoE, may mediate the high affinity binding of lactoferrin and block the binding of beta-VLDL to the remnant receptor efficiently.