Effects of ethanol on receptor-mediated endocytosis in the liver.

Ethanol administration impairs multiple aspects in the process of receptor-mediated endocytosis (RME) in the liver. Studies from our laboratory over the last 10 years have carefully examined RME by the hepatocyte-specific asialoglycoprotein receptor (ASGP-R). We have identified a time course for ethanol-induced defects in RME and established that many of the impairments occur initially in the centrilobular region of the liver and as early as one week after ethanol administration. Impaired intravesicular acidification in ethanol-fed animals has been identified, and these defects in acidification could alter multiple protein trafficking pathways including RME. In addition to altered acidification, altered receptor function (including receptor inactivation) could also contribute to impaired trafficking. Current studies in our laboratory are aimed at an examination of posttranslational modifications in the receptor (acylation and phosphorylation) that are known to affect its function. A role for the ASGP-R in the process of alcoholic apoptosis is also being examined because proper functioning of the ASGP-R is thought to be important in clearance of apoptotic cells.

Suppressive effect of ethanol on the expression of hepatic asialoglycoprotein receptors augmented by interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha.

Blood levels of inflammatory-related cytokines, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, are elevated in patients with alcoholic liver diseases. We investigated the effects of these cytokines and ethanol on the expression of hepatic asialoglycoprotein receptors (AGPRs) in a human hepatoblastoma cell line, HepG2. An [125I]-asialo-orosomucoid binding assay showed significant increases in surface AGPR numbers in HepG2 cells by treatment with IL-1beta, IL-6, and TNF-alpha, to levels which were approximately 130% of the values in untreated control cells. However, the enhanced AGPR numbers induced by treatment with these cytokines were markedly suppressed, to 70%-80% of the number in the untreated cells, by treatment with ethanol. Immunological detection of AGPR with a specific antibody demonstrated that the modulation of surface AGPR numbers was correlated with the cellular expression levels of AGPR. These results suggest that, although IL-1beta, IL-6, and TNF-alpha stimulate the synthesis of hepatic AGPR, ethanol suppresses the expression of AGPR augmented by these cytokines. This leads to an increase in serum asialo-orosomucoid levels caused by the disordered catabolism mediated by AGPR in patients with alcoholic liver disease.