CIRCULATING CELLULAR FIBRONECTIN MAY BE A NATURAL LIGAND FOR THE HEPATIC ASIALOGLYCOPROTEIN RECEPTOR - POSSIBLE PATHWAY FOR FIBRONECTIN DEPOSITION AND TURNOVER IN THE RAT-LIVER

It has been postulated that the in vivo removal of many plasma glycopr oteins after desialylation is mediated by their interaction with a spe cific endocytic receptor on hepatocytes called the asialoglycoprotein receptor (ASGP-R), which is known to have a high affinity for specific carbohydrate residues, such as galactose. However, this mechanism has never been proven in vivo, nor has a naturally occurring ligand for t he ASGP-R been identified. We investigated the influence of the termin al galactose residues on plasma fibronectin (pFn) on its liver deposit ion and turnover in adult rats, using neuraminidase to remove sialic a cid residues to expose galactose residues. We also tested the hypothes is that the normal presence of a large amount of terminal galactose re sidues in cellular Fn (cFn) may allow cFn to serve as a natural ligand readily able to interact with the ASGP-R, In contrast to the slow cle arance of normal pFn from the blood, cFn and desialylated pFn (aFn) di splayed a rapid plasma clearance (P < .001) with greater than 50% of b oth the I-125-cFn or I-125-aFn depositing in the liver within 15 minut es. The enhanced plasma removal and liver deposition of both I-125-cFn and I-125-aFn was competitively inhibited (P <.01) by prior intraveno us infusion of excess asialofetuin, which can selectively bind to the ASGP-R, The enzymatic addition of terminal sialic acid residues onto c Fn to ''mask'' or ''cap'' the normally exposed galactose residues dela yed the rapid plasma removal of cFn, Accelerated degradation of I-125- aFn and I-125-cFn as compared with I-125-pFn was demonstrated in vitro by both primary cultures of normal rat hepatocytes or incubated (37 d egrees C) tissue slices of livers harvested from normal rats after in vivo preloading with tracer I-125-Fn forms. Thus, the ASGP-R appears t o directly participate in the rapid in vivo removal of cFn from the bl ood, while native pFn may be removed by an alternative pathway unless it can become desialylated in vivo. These findings suggest that cFn ma y be a naturally occurring ligand that does not require desialylation before removal by the ASGP-R on hepatocytes.