The mammalian asialoglycoprotein receptor (ASGPR) is located on the sinusoidal membrane of hepatocytes where it binds and endocytoses galactose- terminated glycoproteins (asialoglycoproteins). ASGPR is composed of two highly homologous subunits, termed hepatic lectin 1 and 2. Despite numerous studies the contribution of both subunits to biosynthesis and functional activity of ASGPR in vivo has remained controversial. Mice lacking the murine hepatic lectin (MHL)-2 subunit are viable and fertile without obvious phenotypic abnormalities. In the absence of MHL-2, knockout mice express MHL- 1 protein at reduced levels. Here, we examine the intracellular fate and function of this remaining subunit. The results show that MHL-1 reaches the hepatocellular surface in knockout mice but is unable to effectively remove any one of three different radiolabeled ligands within 30 min. A small but detectable residual ligand clearance in knockout mice at 4 h is apparently not mediated by remaining MHL-1. Serum concentrations of galactose- terminating glycoproteins are not elevated in these ASGPR-deficient mice. However, competitive in vitro degradation experiments suggest that other endogenous ASGPR ligands, the nature of which remain to be determined, accumulate in serum of knockout animals.
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