Antibodies Against the Hepatic Asialoglycoprotein Receptor Perfused In Situ Preferentially Attach to Periportal Liver Cells in the Rat

Abstract

Autoantibodies reacting with the galactose-specific hepatic asialoglycoprotein receptor--a liver-specific component expressed on the surfaces of hepatocytes--are often found in patients with chronic active hepatitis of presumed autoimmune origin. As part of an investigation into whether these anti-asialoglycoprotein receptor antibodies might be involved in the development of periportal liver damage in chronic active hepatitis, livers of ether-anesthetized rats were perfused in situ with polyclonal guinea pig anti-rabbit asialoglycoprotein receptor or murine monoclonal anti-human galactose-specific hepatic asialoglycoprotein receptor antibodies in excess at less than 8 degrees C or, as a control, with guinea pig anti-human plasma protein antibodies or normal guinea pig serum. Rapid (1 min) antegrade (by way of portal vein) or retrograde (through hepatic veins by way of vena cava) perfusions were performed in a nonrecirculating (once-through) mode in Ca+(+)-free medium. Blocks of liver tissue were immediately snap-frozen and the distribution of the antibody examined in cryostat sections by using an avidin-biotin immunohistochemical technique. In all of the perfusions with anti-asialoglycoprotein receptor (six antegrade, seven retrograde), the antibodies were found to be prominently and almost exclusively deposited on liver cells in the periportal areas. No deposition of immunoglobulins was detected in livers perfused with the control guinea pig sera. The findings suggest that the asialoglycoprotein receptor is expressed at high density mainly on cells in zone 1 of the hepatic lobule, and this may have implications for the development of periportal liver damage in chronic active hepatitis.

Auto-antibodies to the asialoglycoprotein receptor in sera of children with auto-immune hepatitis

“…Anti-ASGP-R antibodies are more frequently found in sera from adults with AIH with severe inammatory activity [11,15] and bind preferentially to periportal hepatocytes [12], possibly explaining the characteristic``piece-meal'' necrosis observed in liver biopsies from patients with AIH. ASGP-R do not appear to be preferentially located in the periportal region but rather in the centrolobular region [16]; however, anti-ASGP-R antibodies may also preferentially bind to periportal hepatocytes in vivo given that antibodies in Table 1 Clinical and laboratory ®ndings in ASGP-R positive and ASGP-R negative children with AIH (NS not signi®cant)…”

Altered Zonal Expression of the Cd26 Antigen (Dipeptidyl Peptidase Iv) in Human Cirrhotic Liver

“…Most molecules studied have been intracellular hepatic enzymes, including the cytochrome P-450 family, carbomoylphosphate synthetase, glutamine synthetase and several other enzymes (26)(27)(28)(29)(30)(31)(32). Some cell surface molecules such as the asialoglycoprotein receptor are also zonally distributed, with preferential expression in zone 1 rather than in zones 2 and 3 (33). In addition, bile canalicular brush border enzymes, ATPase and y -glutamyl transferase have been reported to be zonally distributed, with predominant expression in zone 1 (34)(35).…”

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

“…Some ear lier reports provided evidence for a hetero geneous acinar binding of asialo-alkaline phosphatase, preferentially in zone 3 [36,37], epidermal growth factor [35] and asialoorosomucoid (ASOR) in zone 1 [12] in rat liver, whereas insulin, IgA and apolipoprotein B are homogeneously distributed upon injection [116]. The finding of McFarlane et al [125] that antibodies against the ASGP receptor predominantly bind in zone 1 is in contradiction with the results of van der Sluijs et al who further investi gated the acinar distribution of the ASGPprocessing system using 125I-ASOR in antegradely and retrogradely perfused rat livers, by performing quantitative autoradiography [12], A gradient was observed descending from zone-1 to zone-3 cells upon perfusion in the normal direction. The zone-3 to zone-1 gradient observed in the retrograde perfusions was significantly steeper than the zone-1 to zone-3 gradient in antegrade per fusions ( fig.…”