Ethanol-impaired hepatic protein trafficking: Concepts from the asialoglycoprotein receptor system

Objectives: Alcohol abuse with its resulting liver injury is a major health problem worldwide. Recent studies have shown that the process of receptor-mediated endocytosis (RME) is especially susceptible to the deleterious effects of ethanol. Design and methods: In our laboratory, we have shown that after as early as 1 week of ethanol administration, binding, internalization and degradation of asialoorosomucoid, a ligand for the asialoglycoprotein receptor (ASGP-R), is significantly impaired. We have also demonstrated that ethanol administration impairs ATP-dependent acidification of prelysosomal endosomes. Results: These impairments are seen using ligands internalized by the non-specific process of fluid phase endocytosis as well as those internalized by coated pit endocytosis. In addition, we have identified ethanol-induced alterations in post-translational modifications of the receptor including phosphorylation and fatty acid modification (palmitoylation). Conclusions: Impaired function of this receptor could lead to alterations of membrane internalization events after ethanol administration and contribute to ethanol-induced alterations in protein trafficking and signaling in the liver.