Selective hepatic uptake of human β-hexosaminidase A by a specific glycoprotein recognition system on sinusoidal cells

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Abstract
I.v. administered 125I-labeled human .beta.-hexosaminidase A (.beta.-N-acetylglucosaminidase; 2-acetamido-2-deoxy-.beta.-D-glucoside acetamidodeoxyglucohydrolase, EC 3.2.1.30) was rapidly cleared from the circulation of rats and accumulated in the liver. Hepatic cells were subsequently isolated and the label was recovered from both sinusoidal cells and, to a lesser extent, hepatocytes. Clearance was inhibited by the simultaneous infusion of mannan but not by a galactose-terminated glycoprotein. Studies in vitro, in which 125I-.beta.-hexosaminidase was incubated with isolated hepatic cells, detected no uptake of the labeled ligand by hepatocytes. Uptake by sinusoidal cells was temperature dependent and approached saturability. Prior treatment of sinusoidal cells with pronase resulted in markedly decreased uptake of 125I-.beta.-hexosaminidase by these cells. Mannan and partially deglycosylated glycoproteins bearing terminal non-reducing N-acetylglucosamine or mannose residues were potent inhibitors of the cellular uptake of 125I-.beta.-hexosaminidase; native orosomucoid and desialylated (galactose-terminated) orosomucoid were not inhibitory. Of 6 simple sugars tested [mannose, N-acetylglucosamine, lactose, galactose, glucose and mannose-6-phosphate], only mannose was an effective inhibitor of the cellular uptake of 125I-.beta.-hexosaminidase. The kinetics of uptake of .beta.-hexosaminidase and mannose-terminated orosomucoid by sinusoidal cells were similar. The hepatic uptake of the lysosomal glycosidase .beta.-hexosaminidase A is apparently mediated by a receptor on sinusoidal cells which recognizes and binds mannose-terminated glycoproteins.