title: Impaired receptor-mediated endocytosis by the asialoglycoprotein receptor in ethanol-fed mice: implications for studying the role of this receptor in alcoholic apoptosis.
abstract: 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 uptake/clearance of apoptotic cells in vitro. This suggests a potential 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.
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-2000, USA.
authors.forename: Shana R
authors.initials: SR
authors.lastname: Dalton
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wiegert
authors.forename: Cheryl R
authors.initials: CR
authors.lastname: Baldwin
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kassel
authors.forename: Carol A
authors.initials: CA
authors.lastname: Casey
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D037263:Asialoglycoprotein Receptor / Q000502:physiology*; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007457:Iodine Radioisotopes; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice
chemical_list: D037263:Asialoglycoprotein Receptor; D007457:Iodine Radioisotopes; D000431:Ethanol