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Circulating cellular fibronectin may be a natural ligand for the hepatic asialoglycoprotein receptor: Possible pathway for fibronectin deposition and turnover in the rat liver
Author(s) -
Rotundo Robert F.,
Rebres Robert A.,
MckeownLongo Paula J.,
Blumenstock Frank A.,
Saba Thomas M.
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510280227
Subject(s) - asialoglycoprotein receptor , fibronectin , chemistry , microbiology and biotechnology , ligand (biochemistry) , receptor , biochemistry , biology , extracellular matrix , hepatocyte , in vitro
It has been postulated that the in vivo removal of many plasma glycoproteins after desialylation is mediated by their interaction with a specific 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 the ASGP‐R been identified. We investigated the influence of the terminal galactose residues on plasma fibronectin (pFn) on its liver deposition and turnover in adult rats, using neuraminidase to remove sialic acid residues to expose galactose residues. We also tested the hypothesis that the normal presence of a large amount of terminal galactose residues 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 clearance of normal pFn from the blood, cFn and desialylated pFn (aFn) displayed a rapid plasma clearance ( P < .001) with greater than 50% of both the 125 I‐cFn or 125 I‐aFn depositing in the liver within 15 minutes. The enhanced plasma removal and liver deposition of both 125 I‐cFn and 125 I‐aFn was competitively inhibited ( P < .01) by prior intravenous infusion of excess asialofetuin, which can selectively bind to the ASGP‐R. The enzymatic addition of terminal sialic acid residues onto cFn to “mask” or “cap” the normally exposed galactose residues delayed the rapid plasma removal of cFn. Accelerated degradation of 125 I‐aFn and 125 I‐cFn as compared with 125 I‐pFn was demonstrated in vitro by both primary cultures of normal rat hepatocytes or incubated (37°C) tissue slices of livers harvested from normal rats after in vivo preloading with tracer 125 I‐Fn forms. Thus, the ASGP‐R appears to directly participate in the rapid in vivo removal of cFn from the blood, while native pFn may be removed by an alternative pathway unless it can become desialylated in vivo . These findings suggest that cFn may be a naturally occurring ligand that does not require desialylation before removal by the ASGP‐R on hepatocytes.