S-adenosylmethionine (SAMe) is vital to normal cell function as the principal biological methyl donor. The enzyme responsible for SAMe biosynthesis is methionine adenosyltransferase (MAT). Of the two genes (MAT1A, MAT2A) that encode MAT, MAT1A is mainly expressed in adult liver. Cirrhotic patients have decreased hepatic MAT 1A mRNA levels and SAMe biosynthesis. Recently we showed the importance of MAT IA in maintaining a normal liver phenotype using the MAT1A null mice. At 3 months, /vIAT1A null mice have reduced hepatic SAMe and GSH levels, hyperplasia, oxidative stress, increased cytochrome P4502E1 (CYP2EI) and uncoupling protein 2 (UCP2) expressions and are prone to liver injury. On a normal diet, MAT1A null mice develop steatohepatitis by 8 months and hepatocellular carcinoma by 18 months. We found that SAMe plays a central role in regulating hepatocyte cell growth and death. SAMe blocks the mitogenic effect of hepatocyte growth factor and inhibits cell cycle progression. SAMe is anti-apoptotic in normal hepatocytes but pro-apoptotic in hepatoma cells. Taken together, our data suggest that normal hepatic SAMe level favors the differentiated state of hepatocytes, blocks apoptosis and prevents cell proliferation. A fall in hepatic SAMe level facilitates liver regeneration but if this condition persists, predisposes to liver injury, steatohepatitis and finally, cancer. This application represents a logical extension of our work and if successfully accomplished, will greatly enhance our understanding of the role of SAMe in liver biology and pathology and its role as a therapeutic agent.
The aims are: 1) examine SAMe's effect on cell cycle progression - examine effect on cyclins, cyclin-dependent kinases and their inhibitors in both normal and cancerous hepatocytes; 2) elucidate SAMe's differential effect on apoptosis in normal versus cancerous liver cells - using genomics, proteomics and bioinformatics to identify target genes and proteins that may be responsible; 3) investigate how hepatic SAMe deficiency leads to increased CYP2E1 and UCP2 expression and oxidative stress - examine the molecular mechanism(s) of their induction using MAT1A null mice; 4) examine effects of chronic hepatic SAMe deficiency on CCI4-induced liver fibrosis and SAMe treatment in the absence of MAT1A - examine whether hepatic SAMe deficiency predisposes to fibrosis and whether SAMe's therapeutic effect requires the presence of MATIA; 5) elucidate mechanisms of malignant degeneration in MAT1A knockout mice and possible synergy with p53 knockout - examine the roles of p53 and oval cells as contributing factors to malignant degeneration.
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