Hepatic fibrosis is characterized by an increase in type I collagen deposition which alters the normal architecture of the liver leading to liver dysfunction. Many etiologies have been associated with hepatic fibrosis with chronic alcohol consumption being the leading cause of liver fibrosis in the United States. The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess synthesis of collagen during fibrosis. Following exposure to alcohol, the HSC undergoes a transformation from a quiescent, vitamin A storing cell to that of an activated, collagen producing myofibroblast-like cell. In addition to the effects of alcohol on the HSC, alcohol also induces oxidative stress which plays a key role in alcoholic liver disease. The metabolism of ethanol leads to the production of free radicals that have been linked to the development of alcohol-induced liver injury. Thus, diminishing oxidative damage by the use of antioxidants may serve as successful therapeutic treatments for liver diseases caused by numerous agents including alcohol. S-adenosyI-L-methionine (SAMe), the precursor of glutathione, has potential usefulness as an antioxidant. SAMe has been shown to improve hepatic fibrosis; however, the molecular mechanisms of SAMe in liver disease is not well understood. The role of SAMe as an antioxidant implicates redox-sensitive transcription factors such as nuclear factor kappa B (NFkB) and activator protein-1 (AP-1) as being key players which may mediate the antioxidative effects of SAMe and protect the liver against oxidative damage. Additionally, since oxidative stress can lead to inflammation, the effects of SAMe on TNF-alpha and other cytokines (such as IL-6 and IL-10) gene expression would be important, especially considering that these cytokines also modulate collagen expression. Thus, this proposal is aimed at investigating the molecular mechanisms of the antioxidant SAMe on activation of NFkB and AP-1, and expression of TNF-alpha, IL-6 and IL-10 in the HSC. The results of these studies will aid in the development of novel therapeutics aimed at preventing the progression of oxidative-induced hepatic fibrosis.
| McKillop, Iain H; Schrum, Laura W (2005) Alcohol and liver cancer. Alcohol 35:195-203 |
