Chronic Ethanol Consumption Impairs Receptor-Mediated Endocytosis of MAA-Modified Albumin by Liver Endothelial Cells

Authors

Michael J. Duryee, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE
Lynell W. Klassen, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE
Thomas L. Freeman, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE
Monte S. Willis, Department of Pathology, UT Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390-9072, USA
Dean J. Tuma, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NE
Geoffrey M. Thiele, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, NEFollow

Date of this Version

2003

Comments

Published in Biochemical Pharmacology 66 (2003) 1045–1054.

Abstract

Alcoholic liver disease has been associated with abnormalities in receptor-mediated endocytosis (RME) which results in abnormal degradation of metabolically altered proteins. Model systems using formaldehyde-modified albumin (f-Alb) have shown an impairment in RME following chronic alcohol consumption utilizing both in situ perfused rat livers and isolated rat liver endothelial cells (LECs). The discovery that alcohol metabolite derived aldehydes can modify proteins prompted a study to determine if malondialdehyde– acetaldehyde-modified albumin (MAA-Alb) would be degraded similar to that reported for f-Alb, and whether ethanol-fed rats would demonstrate an impaired RME with respect to this ligand which occurs as a consequence of chronic ethanol consumption.
MAA-Alb was degraded slightly more than f-Alb in both in situ perfused livers and at the single cell level. This degradation was completely inhibited with 100x unlabeled f-Alb, which suggests the use of a similar receptor. Following alcohol consumption there was a 50–60% decrease in MAA-Alb degradation in whole livers and isolated LECs. Utilizing isolated LECs it was determined that impairment in internalization was the most likely mechanism for the decrease in the amount of MAA-Alb that was degraded. These data show that chronic alcohol consumption by rats does in fact impair RME of alcohol metabolite-derived adducted proteins, and this impairment is due to a defect in the post-internalization step rather than the binding or degradation of the modified protein.