Our previous studies have indicated that chronic ethanol administration markedly impairs the process of receptor-mediated endocytosis of a representative asialoglycoprotein, asialoorosomucoid (ASOR), by the liver. These proposed studies will continue to explore this phenomenon and, in this regard, the following hypothesis has been formulated: """"""""Ethanol impairs the process of receptor-mediated endocytosis and thereby alters both protein trafficking and processing in the hepatocyte. This impairment could contribute to the pathogenesis of alcoholic liver injury."""""""" The initial objective of our study is to clarify the time of onset of ethanol-induced changes in receptor-mediated endocytosis as well as to establish the time course for recovery to normal endocytotic values. In addition, we intend to gain information on the synthesis and distribution of the asialoglycoprotein receptor in cellular systems of ethanol-fed animals in order to identify a possible mechanism(s) responsible for the impairment of surface binding of asialoglycoproteins as previously reported.
A third aim i s to characterize the effect of ethanol feeding on initial binding and internalization of ASOR. Characterization of post-internalization events of the ASOR- receptors complex will be the goal of the fourth Specific Aim. The purpose of the studies in Specific Aims 3 and 4 is to characterize not only the initial internalization defect but also to identify possible sites of defective intracellular processing of receptor and ligand. A final objective represents an intial attempt to establish the role of receptor-mediated enodcytosis in liver injury; in this regard, we will investigate whether differences exist in the effect of ethanol on RME in hepatocytes isolated in different regions of the liver. Periportal cells are present in the proximal half of the liver acini, while perivenule cells are present in the distal half; the latter cells are thought to be more susceptible to ethanol-induced liver injury. If impaired RME does play a role in the pathogenesis of alcoholic liver disease, we expect that the onset and magnitude of the defect should be more prevalent in the perivenular region. These proposed studies should give valuable information concerning the basic molecular mechanisms of alcohol-induced hepatotoxicity.
| Dalton, Shana R; Lee, Serene M L; King, Rachel N et al. (2009) Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice. Biochem Pharmacol 77:1283-90 |
