EFFECT OF ETOH ON RECEPTOR-MEDIATED ENDOCYTOSIS IN LIVER

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 is 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.