The long-term objective of my work is to characterize at the biochemical level the liver-associated pathology which results from chronic ethanol consumption. The major emphasis will be an investigation of those biochemical changes that occur in cellular energy metabolism during the early (fatty liver) stage of ethanol-induced liver disease. The project described in this proposal is designed to 1) determine how much the ATP-synthesizing system is altered by chronic ethanol consumption, 2) provide information on the mechanism by which ethanol elicits damage to mitochondria, and 3) determine the effects of such damage on cellular energy metabolism. Studies in our laboratory ot date indicate that among all the ethanol-related alterations in hepatic mitochondria it is 1) the lowered activity of the ATP synthetase complex, 2) decreased energy conservation in the NADH-ubiquinone reductase segment of the electron transport chain, and 3) increased fragility of the organelle that are most likely responsible for decreased ATP synthesis by the total mitochondrial complement in the fatty liver. We have thus selected these three lesions for further investigations. Ethanol-related alterations in the polypeptide-phospholipid structure of the ATP synthetase will be determined. The ethanol-elicited changes in the ability of the NADH-ubiquionone reductase complex to drive the formation of an electrochemical proton gradient will be characterized in further detail. Experiments are also designed to determine the effects of the increased fragility of hepatic mitochondria from ethanol-fed rats. Included are measurements os hepatic mitochondria turnover. The above will be combined with investigations of ethanol-related alterations in liver energy metabolism carried out with hepatocytes and in situ liver. The degree to which the energy state of the liver is decreased by chronic ethanol consumption will be investigated in intact liver in situ and in hepatocytes, utilizing 31P NMR spectroscopy to determine cellular phosphorylation potential. Ethanol-elicited functional alterations in the mitochondrion in vivo will be assessed by measurements of the protonmotive force generated by mitochondria inside the hepatocyte.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA002887-09
Application #
3108802
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1980-01-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Ivester, Priscilla; Roberts 2nd, L Jackson; Young, Tracey et al. (2007) Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis. Alcohol Clin Exp Res 31:144-55
Ivester, Priscilla; Shively, Carol A; Register, Thomas C et al. (2003) The effects of moderate ethanol consumption on the liver of the monkey, Macaca fascicularis. Alcohol Clin Exp Res 27:1831-7
Cunningham, Carol C; Van Horn, Cynthia G (2003) Energy availability and alcohol-related liver pathology. Alcohol Res Health 27:291-9
Young, Tracey A; Cunningham, Carol C; Bailey, Shannon M (2002) Reactive oxygen species production by the mitochondrial respiratory chain in isolated rat hepatocytes and liver mitochondria: studies using myxothiazol. Arch Biochem Biophys 405:65-72
Bailey, S M; Patel, V B; Young, T A et al. (2001) Chronic ethanol consumption alters the glutathione/glutathione peroxidase-1 system and protein oxidation status in rat liver. Alcohol Clin Exp Res 25:726-33
Van Horn, C G; Ivester, P; Cunningham, C C (2001) Chronic ethanol consumption and liver glycogen synthesis. Arch Biochem Biophys 392:145-52
Cunningham, C C; Ivester, P (1999) Chronic ethanol, oxygen tension and hepatocyte energy metabolism. Front Biosci 4:D551-6
Cunningham, C C; Spach, P I (1994) Alcoholism and myocardial energy metabolism. Alcohol Clin Exp Res 18:132-7
Coleman, W B; Cahill, A; Ivester, P et al. (1994) Differential effects of ethanol consumption on synthesis of cytoplasmic and mitochondrial encoded subunits of the ATP synthase. Alcohol Clin Exp Res 18:947-50
Cunningham, C C; Spach, P I (1987) The effect of chronic ethanol consumption on the lipids in liver mitochondria. Ann N Y Acad Sci 492:181-92

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