Liver disease due to alcohol is both a serious and prevalent complication of alcohol abuse. At present, there is little specific treatment to offer patients with alcoholic liver disease except to advise abstinence. Unfortunately, sustained abstinence is impossible for most alcoholics; and development of other successful treatments for alcoholic liver injury has been hampered by a lack of understanding about the pathophysiology of liver injury and recovery in patients with alcoholic liver disease. A better understanding of the effect of ethanol consumption on liver injury and clarify the pathogenesis of chronic liver disease in the alcoholic patient. This proposal will begin to explore the effects of ethanol on polyamine synthesis and proto-oncogene expression, two processes essential for liver regeneration. Preliminary data indicate that chronic consumption of ethanol inhibits polyamine synthesis by inhibiting the activity of ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis. Acute treatment with ethanol also inhibits expression of the proto-oncogene c-myc. This proposal will: 1) define the mechanism by which chronic ethanol treatment inhibits ODC activity by determining ethanol effects on ODC apoenzyme levels and post- translational enzyme inhibitory processes (e.g., phosphorylation); 2) determine whether chronic ethanol treatment alters the expression of c- myc and/or other proto-oncogenes (c-fos, P-53, ras) associated with liver regeneration and; 3) test whether ethanol effects on polyamine synthesis and proto-oncogene expression and related to each other or to ethanol associated inhibition of liver regeneration. The results of this project will enhance general knowledge about regulation of regenerative growth and may also suggest rational, new treatment for alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AA008260-01
Application #
3452851
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1989-09-29
Project End
1990-06-30
Budget Start
1989-09-29
Budget End
1990-06-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
George Washington University
Department
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
Fiorino, A S; Diehl, A M; Lin, H Z et al. (1998) Maturation-dependent gene expression in a conditionally transformed liver progenitor cell line. In Vitro Cell Dev Biol Anim 34:247-58
Rai, R M; Yang, S Q; McClain, C et al. (1996) Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats. Am J Physiol 270:G909-18
Diehl, A M; Yang, S Q; Yin, M et al. (1995) Tumor necrosis factor-alpha modulates CCAAT/enhancer binding proteins-DNA binding activities and promotes hepatocyte-specific gene expression during liver regeneration. Hepatology 22:252-61
Silverman, A L; Smith, M R; Sasaki, D et al. (1994) Altered levels of prothymosin immunoreactive peptide, a growth-related gene product, during liver regeneration after chronic ethanol feeding. Alcohol Clin Exp Res 18:616-9
Diehl, A M; Yang, S Q (1994) Regenerative changes in C/EBP alpha and C/EBP beta expression modulate binding to the C/EBP site in the c-fos promoter. Hepatology 19:447-56
Diehl, A M; Michaelson, P; Yang, S Q (1994) Selective induction of CCAAT/enhancer binding protein isoforms occurs during rat liver development. Gastroenterology 106:1625-37
Diehl, A M; Yin, M; Fleckenstein, J et al. (1994) Tumor necrosis factor-alpha induces c-jun during the regenerative response to liver injury. Am J Physiol 267:G552-61
Akerman, P A; Cote, P M; Yang, S Q et al. (1993) Long-term ethanol consumption alters the hepatic response to the regenerative effects of tumor necrosis factor-alpha. Hepatology 17:1066-73
McClain, C; Hill, D; Schmidt, J et al. (1993) Cytokines and alcoholic liver disease. Semin Liver Dis 13:170-82
Lin, F T; MacDougald, O A; Diehl, A M et al. (1993) A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity. Proc Natl Acad Sci U S A 90:9606-10

Showing the most recent 10 out of 12 publications