transforming-growth-factor-alpha and Liver-Cirrhosis--Alcoholic

Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Before alcoholic liver fibrosis becomes evident, the liver undergoes several stages of alcoholic liver disease including steatosis and steatohepatitis. Although the main mechanisms of fibrogenesis are independent of the etiology of liver injury, alcoholic liver fibrosis is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of cell-toxic and profibrogenic ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Although to date removal of the causative agent, i.e. alcohol, still represents the most effective intervention to prevent the manifestation of alcoholic liver disease, sophisticated molecular approaches are underway, aiming to specifically blunt profibrogenic signaling pathways in liver cells or specifically induce cell death in activated hepatic stellate cells to decrease the scarring of the liver.

Topics: Cytochrome P-450 CYP2E1; Ethanol; Female; Gene Expression Regulation; Hepatocytes; Humans; Liver Cirrhosis, Alcoholic; Male; Molecular Biology; Oxidative Stress; Polymerase Chain Reaction; Polymorphism, Genetic; RNA, Messenger; Sensitivity and Specificity; Signal Transduction; Transforming Growth Factor alpha

Liver fibrosis often develops in alcoholic liver diseases without accompanying inflammation; however, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for alcoholic liver diseases, we previously found that ethanol exposure causes HepG2 cells to secrete an approximately 6,000 Da nonheparin-binding polypeptide that stimulates collagen synthesis in human IMR-90 fibroblasts. The aim of the current study was to characterize and identify this factor.. Concentration of type I procollagen peptide and transforming growth factor (TGF)-alpha was assessed by enzyme-linked immunosorbent assay. TGF-alpha protein expression was examined by Western blot. Type I collagen messenger RNA expression in rat hepatic stellate cells was assessed by reverse transcription-polymerase chain reaction.. The collagen-stimulating activity in conditioned media from ethanol-exposed HepG2 cells to stimulate type I procollagen peptide synthesis of IMR-90 cells was specifically inhibited by addition of anti-TGF-alpha antibodies. Western blot analysis showed increased TGF-alpha protein expression in ethanol-treated HepG2 cells. TGF-alpha in conditioned medium from ethanol-exposed HepG2 cells stimulated type-I collagen messenger RNA expression in rat hepatic stellate cells.. These results suggest that TGF-alpha derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver diseases.

Topics: Blotting, Western; Collagen; Collagen Type I; Culture Media, Conditioned; Ethanol; Gene Expression; Hepatoblastoma; Hepatocytes; Humans; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor alpha; Tumor Cells, Cultured; Up-Regulation