Methionine adenosyltransferase (MAT) is a critical enzyme responsible for the biosynthesis of S-adenosylmethionine (SAM). Of the two genes (MAT1A, MAT2A) that encode MAT, MAT1A is mainly expressed in adult liver. Due to differences in kinetics and regulatory properties, cells expressing MAT1A have much higher SAM levels than cells expressing MAT2A. Cirrhotic patients have decreased hepatic MAT activity and SAM biosynthesis. SAM has been used therapeutically but the molecular targets remain unclear. Recently we showed the importance of MAT1A in maintaining a normal liver phenotype using the MAT1A null mice. Three-month old MAT1A null mice have reduced hepatic SAM and GSH levels, hyperplasia, spontaneous oxidative stress, increased cytochrome P4502E1 (CYP2E1) expression and are prone to liver injury. On a normal diet, MAT1A null mice develop non-alcoholic steatohepatitis by 8 months and hepatocellular carcinoma by 18 months. Further, we discovered that the once thought to be liver-specific MAT1A is highly expressed in normal pancreas and pancreatic acini. MAT expression undergoes dramatic changes and pancreatic SAM level fall in female mice fed a choline-deficient ethionine supplemented diet (a model of necrotizing pancreatitis). SAM supplementation prevented pancreatic injury in this model and ameliorated injury due to cerulein infusion, a more acute model of pancreatitis. Although pancreatic injury is normally absent in rodents fed ethanol, they are more susceptible to cerulein-induced injury. Pancreatic SAM levels fell during ethanol feeding and may sensitize the organ to further injury. Given these provocative results, we hypothesize that MAT1A null and heterozygous mice are more susceptible to ethanol-induced tissue injury and may serve as a novel model to study the pathogenesis and treatment of these diseases.
The aims of the proposal are: 1) examine the effect of SAM depletion and treatment in ethanol-induced liver injury-examine whether SAM depletion predisposes to ethanol-induced injury and whether SAM is effective therapeutically in the absence of MAT1A; 2) examine the effect of SAM depletion and treatment in ethanol-induced pancreatic injury-examine whether SAM depletion predisposes to ethanol-induced pancreatic injury and the effect of SAM treatment; 3) elucidate the mechanisms of SAM depiction's sensitizing effect on liver injury-examine the role of CYP2E1, mitochondrial GSH and hepatic macrophage activation in SAM depletion s sensitizing effect; 4) identify the molecular targets of SAM's therapeutic effect in alcoholic liver injury-identify targets of SAM using genomics and proteomics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA013847-01
Application #
6555520
Study Section
Special Emphasis Panel (ZAA1-CC (15))
Program Officer
Russo, Denise A
Project Start
2003-03-01
Project End
2008-02-29
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
1
Fiscal Year
2003
Total Cost
$385,172
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Vázquez-Chantada, Mercedes; Ariz, Usue; Varela-Rey, Marta et al. (2009) Evidence for LKB1/AMP-activated protein kinase/ endothelial nitric oxide synthase cascade regulated by hepatocyte growth factor, S-adenosylmethionine, and nitric oxide in hepatocyte proliferation. Hepatology 49:608-17
Tomasi, Maria Lauda; Iglesias-Ara, Ainhoa; Yang, Heping et al. (2009) S-adenosylmethionine regulates apurinic/apyrimidinic endonuclease 1 stability: implication in hepatocarcinogenesis. Gastroenterology 136:1025-36
Lu, Shelly C; Mato, Jose M (2008) S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol 23 Suppl 1:S73-7
Yu, Mimi C; Yuan, Jian-Min; Lu, Shelly C (2008) Alcohol, cofactors and the genetics of hepatocellular carcinoma. J Gastroenterol Hepatol 23 Suppl 1:S92-7
Rountree, C Bart; Senadheera, Shantha; Mato, Jose M et al. (2008) Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficient mice. Hepatology 47:1288-97
Yang, Heping; Ara, Ainhoa Iglesias; Magilnick, Nathaniel et al. (2008) Expression pattern, regulation, and functions of methionine adenosyltransferase 2beta splicing variants in hepatoma cells. Gastroenterology 134:281-91
Martinez-Chantar, M Luz; Vazquez-Chantada, Mercedes; Ariz, Usue et al. (2008) Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology 47:1191-9
Martinez-Lopez, Nuria; Varela-Rey, Marta; Ariz, Usue et al. (2008) S-adenosylmethionine and proliferation: new pathways, new targets. Biochem Soc Trans 36:848-52
Zhou, Wenyun; Alonso, Sergio; Takai, Daisaku et al. (2008) Requirement of RIZ1 for cancer prevention by methyl-balanced diet. PLoS One 3:e3390

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