Hormonal Regulation of Enzyme Levels in Mammalian Tissue

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DESCRIPTION (provided by applicant) The cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) is critical for energy metabolism; it ablation results in death within 2 days after birth, with massive accumulation of lipid in the liver and severe hypoglycemia. The gene for PEPCK-C is expressed in a variety of mammalian tissue, most importantly the liver, adipose tissue and kidney cortex. The role of PEPCK-C in each of these tissues is vital for the proper functioning of energy metabolism in that tissue. In the liver, the gene for PEPCK-C is transcribed in response to alterations in the nutritional status of the animal and is involved in both hepatic gluconeogenesis and glyceroneogenesis. PEPCK-C gene transcription in the liver is mainly controlled by glucagon (acting via cAMP) and glucocorticoids, which stimulate transcription and by insulin, which inhibits transcription. In adipose tissue, PEPCK-C is involved in regulating the rate of fatty acid re-esterification (glyceroneogenesis); the transcription of the gene in that tissue is controlled and by catecholamines, glucocorticoids and insulin. PEPCK-C is a single copy gene, so that the differential regulation of transcription is the result of a combination of transcription factors and co-activators that control gene expression; some are tissue-specific, while others are shared by all three tissues. The goal of this research is to delineate the factors that are involved in this process and to develop a model that integrates the hormonal regulation of PEPCK-C gene transcription in specific tissues with the physiological role of the enzyme in animals. We will concentrate on the regulation of transcription by glucagon, glucocorticoids and insulin in the liver and by glucocorticoids and insulin in the adipose tissue and will develop a model to explain the action of these hormones in the two tissues. This research has special significance to diabetes and obesity, since PEPCK-C is a critical enzyme in both the control of hepatic glucose output and triglyceride deposition in adipose tissue.