Altered hepatic methionine metabolism and hyperhomocysteinemia are well recognized in alcoholic liver disease but the exact mechanisms and pathogenetic consequences are not well defined. The protective mechanisms of SAM in alcoholic liver injury also remain ill defined. We hypothesize that abnormal hepatic methionine metabolism has important pathogenetic consequences in the development of alcoholic liver injury. This hypothesis is based on several novel key findings. First, using the Tsukamoto-French intragastric ethanol-feeding model, we observed a switch in the expression of methionine adenosyltransferase (MAT), the key enzyme that catabolizes methionine to form S-adenosyl-methionine (SAM) in both whole liver and Kupffer cells. In the liver, this was associated with decreased SAM level and global DNA hypomethylation. Second, homocysteine in pathologically relevant concentrations induced the expression of tissue inhibitor of metalloproteinases-4 (TIMP- 1) and a 1(I) procollagen in a hepatic stellate cell line and collagen production in primary cultures of hepatic stellate cells. The current proposal will extend these findings, test several hypotheses and examine the protective mechanisms of SAM.
The aims are: 1) examine changes in hepatic methionine metabolism during the development of ethanol-induced liver injury and the effect of SAM treatment - using the intragastric ethanol and high fat feeding, define stage-specific changes in methionine metabolism, examine key enzymes that affect the steady state SAM and homocysteine levels, investigate consequence of these changes and the effect of SAM treatment; 2) define the role of homocysteine in ethanol-induced liver fibrosis -evaluate the effect of homocysteine on markers of fibrogenesis in primary cultures of stellate cells and examine biological markers such as collagen production and proliferation, test the hypothesis that there is increased homocysteine release from hepatocytes of ethanol-fed animals due to abnormalities in methionine metabolism, which can exert paracrine effects on stellate cells to induce fibrogenesis; 3) examine changes in MAT expression and SAM homeostasis in Kupffer cells during the course of ethanol-induced liver injury and the effect of SAM treatment - test the hypothesis that the switch in MAT expression in Kupffer cells may result in lower SAM level and induce TNF expression, examine the effect of SAM treatment on TNF expression in vitro in LPS-stimulated normal Kupffer cells, ex-vivo in Kupffer cells obtained from ethanol-fed animals, and in vivo, investigate the mechanisms of SAM's suppressive effect on TNF expression.
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