To clarify the important relationship between stellate cells and hepatocytes in the processing of Vitamin A in the liver, we plan: 1) to elucidate sites of control in the uptake metabolism, storage and release of vitamin A, 2) to identify the nature of the intercellular transfer agent for retinol, and 3) to clarify factors which affect both the number and the lipid and protein content of vitamin A-containing globules in stellate cells and hepatocytes. In regard to aim 1, the steady-state pattern of retinol and its major metabolites, as well as their rate of formation from labeled retinyl acetate, will be assessed in isolated stellate cells and in """"""""light"""""""" and """"""""heavy"""""""" hepatocytes. The association of retinol with intracellular components, and the activities of key enzymes acting on retinol within cells, will also be studied as a function of vitamin A status. We will also try to identify physiological feedback inhibitors and activators in serum that control vitamin A metabolism. Finally, we will examine the uptake of several vitamin A analogs by isolated liver cells as well as their ability to stimulate vitamin A storage. Relative to aim 2, the three possibilities that the intercellular transfer agent for vitamin A is a new transfer protein, is retinyl Beta-glucuronide and is cellular retinol-binding protein will be tested. Retinyl fluoride, a new probe of retinoid binding proteins, will be extensively used in these studies. Germane to aim 3, the possibility that the vitamin-A containing globules of hepatocytes and stellate cells may have multiple functions and thereby respond to various dietary lipids, such as cholesterol, vitamin E and high fat intakes, as well as to vitamin A, will be explored.
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