Chronic ethanol abuse is a serious public health problem which has a significant role in the development of liver injury as well as in enhanced susceptibility to HIV and development of AIDS. However, biochemical mechanisms to explain the role of ethanol in the pathophysiology of hepatic injury or AIDS are not completely understood. Increasing evidence suggests that a systemic deficiency of S-adenosylmethionine (Adomet) has a pivotal role in the pathogenesis of both diseases. This proposal will examine this role of Adomet deficiency and will evaluate exogenous Adomet as a therapy in these diseases. Systemic Adomet deficiency was first identified by us as an acquired metabolic disorder in alcoholic subjects. Similar observations were made in animals administered ethanol rich diets. Adomet deficiency results in depletion of the intracellular antioxidant tripeptide glutathione and patients with alcoholic liver disease and AIDS have subnormal plasma glutathione. We postulate that deficiencies of Adomet and glutathione increase intracellular oxidative stress and activate the redox-sensitive transcription factor NFkappaB which increases production of the inflammatory cytokine tumor necrosis factor alpha(TNF). TNF has been postulated to play a role in the development of alcoholic liver disease, the progression of AIDS, and the clinical complications of both processes. Adomet deficiency also alters membrane fluidity and integrity. Further, we propose that exogenous Adomet attenuates glutathione depletion, oxidative stress, NFkappaB, TNF production, and membrane integrity and fluidity. These objectives will be tested by the following specific objectives: (1) Determine changes in hepatic Adomet concentrations and Adomet synthetase activity in animals administered ethanol rich Tsukamoto-French diet and examine whether exogenous Adomet attenuates this liver injury. (2) Determine whether Adomet deficiency produced in three animal models developed in our laboratory - viz., choline deficient, malnourished, or hypoxic - enhances lipopolysaccharide hepatotoxicity and determine whether Adomet supplementation attenuates this injury. (3) Determine whether Adomet administration improves hepatic functions and attenuates cytokine production and immunocompetence in patients with Adomet deficiency. (4) Examine the mechanisms by which Adomet deficiency may increase TNF production and sensitize cells to TNF cytotoxicity. Our long-term goal is to evaluate the effectiveness of Adomet therapy especially since Adomet may not only act as a glutathione precursor but also improve its mitochondrial transport by normalizing membrane functions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010496-03
Application #
2667590
Study Section
Special Emphasis Panel (SRCA (57))
Project Start
1996-03-01
Project End
2000-09-30
Budget Start
1998-03-01
Budget End
2000-09-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Smart, Laura; Gobejishvili, Leila; Crittenden, Neil et al. (2013) Alcoholic Hepatitis: Steroids vs. Pentoxifylline. Curr Hepat Rep 12:59-65
Liu, Yanlong; Wang, Chunhong; Wang, Yuhua et al. (2012) Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells. Toxicol Appl Pharmacol 264:212-21
Kirpich, Irina A; Feng, Wenke; Wang, Yuhua et al. (2012) The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res 36:835-46
Gaetke, Lisa M; McClain, Craig J; Toleman, C Jean et al. (2010) Yogurt protects against growth retardation in weanling rats fed diets high in phytic acid. J Nutr Biochem 21:147-52
Kirpich, Irina A; Solovieva, Natalia V; Leikhter, Svetlana N et al. (2008) Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 42:675-82
Gobejishvili, Leila; Barve, Shirish; Joshi-Barve, Swati et al. (2008) Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 295:G718-24
Chang, Weiyuan; McClain, Craig J; Liu, Marcia C et al. (2008) Effects of 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid on 4-hydroxy-2-nonenal-induced apoptotic T cell death. J Nutr Biochem 19:184-92
de Villiers, Willem J S; Song, Zhenyuan; Nasser, Munira S et al. (2007) 4-Hydroxynonenal-induced apoptosis in rat hepatic stellate cells: mechanistic approach. J Gastroenterol Hepatol 22:414-22
Cave, Matthew; Deaciuc, Ion; Mendez, Christian et al. (2007) Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem 18:184-95
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

Showing the most recent 10 out of 40 publications