Chronic alcohol consumption is a major health problem in the United States and worldwide, but the mechanism(s) responsible for the hepatotoxic effects of ethanol are presently unknown. The cellular processes of membrane biogenesis, protein secretion, and receptor-mediated endocytosis (RME) appear to be especially susceptible to the detrimental effects of ethanol. We have extensively studied the process of RME by the hepatocyte-specific asialoglycoprotein receptor (ASGP-R) and have identified multiple steps of this pathway that are affected by ethanol treatment. Of interest to our laboratory are recent reports identifying cellular fibronectin (cFn) as a naturally occurring ligand for the ASGP-R. Cellular Fn is an isoform of plasma fibronectin (pFn) that is virtually undetectable in normal liver, but is increased in the early phases of fibrotic liver injury. The main cells responsible for this increase are activated liver endothelial cells. Once secreted, the Fn can be cleared by neighboring cells such as hepatocytes via the ASGP-R, or can be deposited into the ECM itself causing adjustments to the normal matrix environment. During insults such as alcohol administration, alterations in these clearance mechanisms might lead to increased levels of cFn, which in turn could contribute to the pathogenesis of fibrosis by activating the hepatic stellate cells (the main producer of extracellular matrix components). Therefore, in order to examine the dynamics of fibronectin (Fn) during alcoholic liver injury and to gain a better understanding of the clinical significance of ASGP-R-mediated clearance of cFn, we propose the following updated hypothesis: Impaired clearance of cellular fibronectin (cFn) mediated by the hepatocytic ASGP-R leads to increased levels of cFn in the liver following chronic ethanol consumption. This increased fibronectin concentration contributes to the pathogenesis of liver injury by its role in the initiation of the fibrogenic cascade