Vitamin A is required by the body for maintaining many important physiological functions including the maintenance of normal growth and development, a healthy immune response, normal reproduction, and normal vision. Owing to the importance of vitamin A in so many essential physiological processes, the body has developed an ability to store vitamin A, primarily in liver but also in adipose tissue. At present, relatively few details are known about the molecular processes responsible for vitamin A storage and metabolism in hepatocytes and hepatic stellate cells, the two liver cell types involved in vitamin A storage and metabolism. Similarly, relatively little is known about the molecular process that are important for mediating vitamin A storage and metabolism in adipocytes, the cell type in adipose tissue responsible for vitamin A accumulation. The investigations proposed in this application are aimed at providing new detailed understanding of these processes. In addition, the proposed investigations will explore the molecular basis for observations which link hepatic vitamin A storage and metabolism with the development of liver disease, including hepatic steatosis and hepatic fibrosis, as well as at explaining observations linking adipose tissue retinoid metabolism to the development of type II diabetes. All of the studies being proposed will be carried out in mice that lack or express in a cell type-specific manner one or more genes involved in mediating vitamin A storage, metabolism and/or actions.
Specific Aim 1 explores the roles that retinol-binding protein (RBP) synthesized specifically in hepatocytes and specifically in HSCs have in the mobilization of hepatic vitamin A stores into the circulation. Preliminary data obtained during the previous period indicate that mice lacking cellular retinol-binding protein, type I (CRBPI), as well as mice lacking both CRBPI and lecithin:retinol acyltransferase, spontaneously develop fatty liver.
Specific Aim 2 will determine the molecular basis for why this occurs. The 3rd Specific Aim will define the role that retinoic acid signaling, as mediated by retinoic acid receptors (RARs), has in maintaining vitamin A and triglyceride storage/metabolism in liver. Data obtained in the previous period indicate that CRBPI may act in facilitating the transfer of postprandial vitamin A from hepatocytes to HSCs where it is stored.
Specific Aim 4 will identify the roles that CRBPI, expressed specifically in hepatocytes or specifically in HSCs, has in mediating postprandial vitamin A accumulation (storage) in the liver.
Specific Aim 5 will define the role of RBP in facilitating vitamin A mobilization for adipocytes and delineating how this is linked to the proposed role of adipose-derived RBP in impairing insulin responsiveness
Vitamin A is required by the body for maintaining many important physiological functions, including the maintenance of normal growth and development, the maintenance of a healthy immune response, the maintenance of normal reproduction, and the maintenance of normal vision. The great public health significance of vitamin A is strongly underscored by World Health Organization estimates that in excess of 100,000,000 children worldwide are at increased risk of morbidity and mortality due to insufficient intake of vitamin A from the diet. Arising out of the importance of vitamin A for maintaining so many essential physiological processes, the body has developed an ability to store vitamin A, primarily in liver but also in adipose tissue. Investigations proposed in this application will focus on defining the molecular events that are important for mediating vitamin A storage in liver and adipose tissue and will explore relationships between hepatic vitamin A storage and the development of liver disease and between adipose tissue vitamin A storage and the development of type II diabetes.
