Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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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.
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