Vitamin E is the primary membrane-localized antioxidant protecting cellular membranes from free radical-induced lipid peroxidation. Infants and children with chronic forms of cholestatic hepatobiliary diseases frequently develop malabsorption and a secondary deficiency of vitamin E, resulting in damage to the nervous system. Preliminary studies also suggest that hepatic clearance of circulating bile acids may be impaired by the vitamin E deficiency state in children with chronic cholestasis and in normal rats, presumably due to alterations in hepatocyte membrane properties essential for transport and secretion of bile acids. This proposal will test the hypothesis that vitamin E influences hepatocyte structure and function in the normal liver and during cholestasis by altering cellular membrane properties. Experimental rat models will be developed with dietary vitamin E deficiency, sufficiency, or excess in combination with and without experimental cholestasis induced by either bile duct-ligation or ethinylestradiol treatment. Isolated hepatocytes will be used to study the effect of vitamin E on hepatocellular function. Taurocholate uptake, NaK-ATPase pump activity, ouabain uptake, and degree of lipid peroxidation will be determined in hepatocytes isolated from each experimental group and controls. In vitro vitamin E repletion of vitamin E-deficient hepatocytes will be performed to assess the reversibility of the impairment in function of vitamin E-deficient hepatocytes. In order to determine if these effects on hepatocyte function are caused by changes in hepatocellular membrane properties, subcellular membranes from each experimental group will be compared in the following manner: cholesterol, cholesteryl esters and total phospholipids content; phospholipid subclasses; fatty acid composition; vitamin E content; conjugated diene content; and membrane fluidity. Finally, light and electron microscopic examination of liver tissue from each group of rats will be used to determine morphological correlates to the functional alterations due to vitamin E deficiency. The results of this study will help characterize the role played by vitamin E in modulating hepatocyte structure and function in the normal liver and during cholestasis and may provide the basis for treatment with vitamin E (or other antioxidant substances) in patients with chronic cholestasis and other liver diseases. Furthermore, a better understanding of the physiologic role of vitamin E in cellular membrane function will be achieved through these proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK038446-02
Application #
3462604
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-05-10
Project End
1992-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Sokol, R J; Taylor, S F; Devereaux, M W et al. (1996) Hepatic oxidant injury and glutathione depletion during total parenteral nutrition in weanling rats. Am J Physiol 270:G691-700
Abdel-Rahman, A; Parks, J K; Devereaux, M W et al. (1995) Developmental changes in newborn lamb brain mitochondrial activity and postasphyxial lipid peroxidation. Proc Soc Exp Biol Med 209:170-7
Sokol, R J; Twedt, D; McKim Jr, J M et al. (1994) Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis. Gastroenterology 107:1788-98
Traber, M G; Sokol, R J; Kohlschutter, A et al. (1993) Impaired discrimination between stereoisomers of alpha-tocopherol in patients with familial isolated vitamin E deficiency. J Lipid Res 34:201-10
Sokol, R J; Devereaux, M W; O'Brien, K et al. (1993) Abnormal hepatic mitochondrial respiration and cytochrome C oxidase activity in rats with long-term copper overload. Gastroenterology 105:178-87
Sokol, R J; Devereaux, M; Khandwala, R et al. (1993) Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes. Hepatology 17:869-81
Sokol, R J; Devereaux, M; Khandwala, R A (1991) Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat. J Lipid Res 32:1349-57
Sokol, R J; Devereaux, M W; Khandwala, R A et al. (1990) Effect of vitamin E on transport processes in isolated rat hepatocytes. J Pediatr Gastroenterol Nutr 11:261-7
Sokol, R J; Devereaux, M; Mierau, G W et al. (1990) Oxidant injury to hepatic mitochondrial lipids in rats with dietary copper overload. Modification by vitamin E deficiency. Gastroenterology 99:1061-71
Sokol, R J (1990) Vitamin E and neurologic deficits. Adv Pediatr 37:119-48

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