The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid, protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014145-04
Application #
7106391
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
2003-08-01
Project End
2008-01-31
Budget Start
2006-08-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2006
Total Cost
$253,769
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Esfandiari, Farah; Medici, Valentina; Wong, Donna H et al. (2010) Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. Hepatology 51:932-41
Villanueva, Jesus A; Esfandiari, Farah; White, Mollie E et al. (2007) S-adenosylmethionine attenuates oxidative liver injury in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin Exp Res 31:1934-43
Esfandiari, Farah; You, Min; Villanueva, Jesus A et al. (2007) S-adenosylmethionine attenuates hepatic lipid synthesis in micropigs fed ethanol with a folate-deficient diet. Alcohol Clin Exp Res 31:1231-9
Wallock-Montelius, Lynn M; Villanueva, Jesus A; Chapin, Robert E et al. (2007) Chronic ethanol perturbs testicular folate metabolism and dietary folate deficiency reduces sex hormone levels in the Yucatan micropig. Biol Reprod 76:455-65
Purohit, Vishnudutt; Abdelmalek, Manal F; Barve, Shirish et al. (2007) Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 86:14-24
Villanueva, Jesus A; Esfandiari, Farah; Wong, Donna H et al. (2006) Abnormal transsulfuration and glutathione metabolism in the micropig model of alcoholic liver disease. Alcohol Clin Exp Res 30:1262-70
Esfandiari, Farah; Villanueva, Jesus A; Wong, Donna H et al. (2005) Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol 289:G54-63
Villanueva, Jesus A; Halsted, Charles H (2004) Hepatic transmethylation reactions in micropigs with alcoholic liver disease. Hepatology 39:1303-10