The main objective of this research proposal is the study of the metabolic functions of mammalian malic enzymes, as well as the mechanisms responsible for the "in vivo" regulation of the enzymic protein. The biggest thrust of the research project will be directed toward a comprehensive study of hepatic malic enzyme and to the mechanisms of its induction by a variety of nutritional and physiological stimuli. The striking and specific induction of the rat liver enzyme which is observed after the administration of a diet devoid of protein will be studied in order to establish both the metabolic role(s) which makes this activation necessary under conditions which do not result in increased lipogenesis, and the nature of the regulatory processes at the cellular and organic level. The effect of different hormones and dietary manipulations on the response will be investigated, in order to gain an understanding of the mechanisms which regulate the concentration of this hepatic enzyme. Both "in vivo" and "in vitro" experiments will be performed, utilizing rats and isolated parenchymal liver cells as well as cultured minimal deviation hepatoma cells for these experiments. The possible involvement of malic enzyme in either a reductive carboxylation of pyruvate or providing reducing equivalents for specific reactions not involved in lipogenesis will also be investigated. the relationships between the synthesis of malic enzyme and other NADPH-generating enzymes as well as fatty acid synthase under different experimental conditions and the mechanism of action of insulin and glucagon will also be studied. It is hoped that these investigations will provide important insights not only into the function of hepatic malic enzyme but also on the regulation of enzyme synthesis in mammalian liver.