Impaired receptor-mediated endocytosis: its role in alcohol-induced apoptosis.
Hepatocyte apoptosis, inflammation, and fibrosis are prominent features of liver disease in general and of alcoholic liver injury in particular. Although the link between these processes remains unclear, one universal characteristic of liver injury is the induction of hepatocellular damage, which results in the generation of apoptotic bodies. Work from our laboratory over the last several years has studied the effect of ethanol administration on the process of apoptosis and a role for altered endocytosis in alcoholic apoptosis. We initially focused our research on the hepatocyte by examining endocytosis using the asialoglycoprotein receptor (ASGP-R) pathway as a model and we identified multiple ethanol-induced impairments in receptor function. We also showed that uptake of apoptotic bodies is impaired in hepatocytes isolated from ethanol-fed animals compared to controls, and that this impairment is linked to altered ASGP-R function. Recent work from our laboratory is examining a link between ethanol-impaired ASGP-R function, apoptotic body accumulation, and inflammation in the liver. We are particularly interested in data showing that factors produced by Kupffer cells incubated with apoptotic bodies can lead to production of tumor necrosis factor-alpha and interleukin-6, and that this effect is exacerbated in the setting of alcohol administration. In addition, we have preliminary data showing that media from Kupffer cell cultures incubated with apoptotic bodies can induce hepatocyte killing. The goal of our future work is to show that inadequate removal of apoptotic cells, in part via altered receptor-mediated endocytosis, plays a role in the course of pathogenesis of alcoholic liver injury.
Casey
Carol A
CA
Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska 68105, USA. ccasey@unmc.edu
Lee
Serene M L
SM
Aziz-Seible
Razia
R
McVicker
Benita L
BL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects* / Q000502:physiology
D000431:Ethanol