TGF-beta signaling in alcohol induced hepatic injury.
Chronic alcohol consumption is a risk factor for the development of chronic liver disease. Ethanol exerts its detrimental effects by various means: Directly via toxic metabolites, and indirectly by affecting the gut barrier leading to elevated levels of endotoxins in the blood challenging the liver. These factors, together with the resulting inflammatory and profibrogenic cytokine production, drive the organ's response, characterized by activation of hepatic stellate cells. Recent evidence argues for other cell types besides hepatic stellate cells, including hepatocytes, as additional sources of fibroblasts producing extracellular matrix and to be responsible for scar formation. Besides mediating hepatocyte apoptosis, TGF-beta additionally induces fibroblastoid transdifferentiation. This process is accompanied with loss of epithelial marker proteins and upregulation of fibrosis related proteins. These findings challenge the current view of the passive role of hepatocytes in liver fibrosis. In line, hepatocyte-specific inhibition of the TGF-beta pathway prevents CCl4 induced liver injury. Hence, this review focuses on the interplay of TGF-beta and alcohol in chronic liver disease with special emphasis on the potential contribution of hepatocytes.
Meyer
Christoph
C
Molecular Hepatology, Alcohol dependent Diseases, II. Medical Clinic, Faculty of Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Meindl-Beinker
Nadja M
NM
Dooley
Steven
S
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002492:Central Nervous System Depressants; D016212:Transforming Growth Factor beta; D000431:Ethanol