Molecular mechanisms of alcohol-induced hepatic fibrosis.
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.
Siegmund
Soren V
SV
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Dooley
Steven
S
Brenner
David A
DA
D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008967:Molecular Biology; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1