The insulin-degrading activity of plasma-membrane fractions from rat liver.

Loss of the labelled glycoproteins from the circulation was very rapid in all cases and was complete within IOmin, more than 80% of the injected label being present in the liver (P. Thomas & M. Jones, unpublished results). An even distribution of labelling was found throughout the liver 15min after intravenous injection of asialo-al-acid glycoprotein, with silver grains deposited mainly over hepatocytes and little or no labelling of Kupffer cells. After 3 h, most of the radioactivity had been lost from the liver. Asialo-carcinoembryonic antigen 1 5 min after intravenous injection also showed extensive labelling of hepatocytes, though some labelling of Kupffer cells could be observed. About 60% of the original radioactivity was still present in the liver after 3h. However, 15min after injection of native carcinoembryonic antigen most of the labelling was associated with the Kupffer cells with little or no label on the hepatocytes. After 60min, both hepatocytes and Kupffer cells were labelled and after 3 h most labelling was on the hepatocytes and appeared to be associated with secondary lysosomes close to the bilecannuliculi. As with asialo-carcinoembryonicantigen, about 60 %of the radioactivity remained in the liver after 3 h. Both asialo-al-acid glycoprotein and asialo-carcinoembryonic antigen showed a marked uptake by hepatocytes, presumably due to recognition of terminal galactose residues by the galactose receptor present on the plasma membrane of the hepatocyte (Ashwell & Morell, 1974). However, the exclusive uptake of native carcinoembryonic antigen by Kupffer cells provides further evidence for the absence of involvement of the hepatocyte galactose receptor (Ashwell & Morell, 1974) and the hepatocyte N-acetylglucosamine receptor (Stockert et al., 1976) in its initial transfer from the circulation to the liver. A time-dependent transfer of native carcinoembryonic antigen from Kupffer cells to hepatocytes was observed, and this may be a similar mechanism to that found in the removal of the haptoglobin-haemoglobin complex from the circulation (Wada et al., 1970).