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Apoptotic cell death is a well-defined process that is controlled by intrinsic cellular mechanisms followed by the generation of apoptotic bodies and their subsequent rapid elimination through the action of phagocytic cells. Within the liver, the asialoglycoprotein receptor (ASGP-R) has been shown to be involved in the phagocytosis of apoptotic hepatocytes, as well as altered cellular endocytic events after ethanol administration. The goal of the present study was to further clarify the capacity of ASGP-R to phagocytose apoptotic cells in relationship to the damaging events that occur with alcohol consumption. For these experiments, we used an in vitro suspension assay coupled with flow cytometry to measure apoptotic cell engulfment by rat hepatocytes after chronic ethanol administration. The results of this assay indicated that the phagocytosis of apoptotic cells was decreased significantly (30% to 42%, P < .05) in the presence of antibody specific for ASGP-R as well as the introduction of competing sugars in the media. In addition, uptake of apoptotic cells was

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During receptor-mediated endocytosis (RME), extracellular molecules are internalized after being recognized and bound to specific cell surface receptors. In previous studies of the asialoglycoprotein receptor (ASGPR) in rats, we showed that ethanol impairs RME at multiple ASGPR sites. Ethanol administration has been shown to increase apoptosis, and we demonstrated increased sensitization to apoptotic induction in hepatocytes from ethanol-fed rats. Although a physiological role for the ASGPR has not been identified, investigators have shown its involvement in the uptakelclearance of apoptotic cells in vitvo. This suggests apotential role for the ASGPR in the removal of apoptotic cells, and the recent availability of an ASGPR-deficient mouse strain provides an excellent opportunity to examine the role of the ASGPR during ethanol impairment. In this study, we examined ethanol-impaired RME in mice and began the characterization of ASGPR-deficient mice for use in ethanol studies. Similar to our findings with rats, ligand binding, internalization, and degradation were decreased 45-50% in hepatocytes from ethanol-fed wild-type mice. In ASGPR-deficient mice, these parameters did not vary among the chow-fed, pair-fed control, or ethanol groups and were negligible compared with those of wild-type mice. TUNEL analysis of liver sections showed an ethanol-induced increase in apoptotic bodies in all mouse strains with a significant difference in the receptor-deficient mice. Further, the livers of ASGPR-deficient mice had three times more apoptotic bodies, in all feeding groups, compared with wild-type mice. These results support the use of the ASGPR-deficient mouse model for studying ethanol-induced liver injury, specifically ethanol-induced apoptosis.

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