Regulation of hepatic gluconeogenesis by hormones such as glucagon, insulin, epinephrine, vasopressin and antiotensin is well established. In contrast, however, relatively few studies have examined the effects of these hormones, on regulation of the various processes involved in energy generation in the liver and heart. It may be expected that stimulation of gluconeogenesis from 3-carbon precursors (e.g. pyruvate and lactate) by glucagon or Alpha-adrenergic agonist, phenylephrine, would decrease the oxidation of these compounds. However, preliminary data indicate that the Alpha-adrenergic agonist, phenylephrine, increases the oxidation of (2-14C) pyruvate both in the perfused rat liver and the perfused working heart preparation, demonstrating that the metabolic flux through the tricarboxylic acid cyle (TCA cycle) is stimulated by Alpha-adrenergic stimulation. Therefore, it is the overall objective of this proposal to characterize and elucidate the effect of epinephrine, vasopressin, angiotensin, glucagon and insulin on the key regulatory processes involved in carbohydrate energy metabolism. Initally studies will be performed to elucidate the effects of the various hormones described above on the metabolic flux through the pyruvate dehydrogenase (PDH) complex and the TCA cycle. These and additional studies with (2-l4C) labeled acetate will indicate whether the increased TCA cycle activity, during for eg. Alpha-adrenergic stimulation of livers and hearts, is a function of increased pyruvate carboxylation or increased metabolic flux through the PDH reaction. Secondly, employing (l-l4C) monomethyl Alpha-ketoglutarate, as a source of intracellular Alpha-ketoglutarate, studies will be performed to investigate the effects of the various hormones on the activity of one of the key regulatory enzymes of the TCA cycle, the Alpha-ketoglutarate dehydrogenase complex in intact perfused rat livers and hearts. Employing this approach to overcome cellular impermeability to free Alpha-ketoglutarate, this will be the initial attempt, thus far, to elucidate directly the regulation of the Alpha-ketoglutarate dehydrogenase complex in an intact perfused organ preparation. Studies in working heart preparations will also investigate the relationship between energy requirements of the tissue (due to alterations in afterload) and activity of the TCA cycle and the Alpha-ketoglutarate dehydrogenase complex. This latter approach will also demonstrate if hormone (eg. epinephrine) elicited metabolic alterations are secondary to the inotropic effects of the hormones.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK035713-01A1
Application #
3233970
Study Section
Metabolism Study Section (MET)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Patel, T B; Nair, B G; Padmini, E et al. (1995) Alterations in messenger RNA encoding atrial natriuretic hormone receptor A and C subtypes during hepatic regeneration. Hepatology 21:1682-9
Rashed, H M; Sun, H; Patel, T B (1993) Atrial natriuretic peptide inhibits growth of hepatoblastoma (HEP G2) cells by means of activation of clearance receptors. Hepatology 17:677-84
Nair, B G; Rashed, H M; Patel, T B (1993) Epidermal growth factor produces inotropic and chronotropic effects in rat hearts by increasing cyclic AMP accumulation. Growth Factors 8:41-8
Nair, B G; Patel, T B (1993) Regulation of cardiac adenylyl cyclase by epidermal growth factor (EGF). Role of EGF receptor protein tyrosine kinase activity. Biochem Pharmacol 46:1239-45
Yu, Y; Nair, B G; Patel, T B (1992) Epidermal growth factor stimulates cAMP accumulation in cultured rat cardiac myocytes. J Cell Physiol 150:559-67
Rashed, H M; Nair, B G; Patel, T B (1992) Regulation of hepatic glycolysis and gluconeogenesis by atrial natriuretic peptide. Arch Biochem Biophys 298:640-5
Rashed, S M; Patel, T B (1991) Regulation of hepatic energy metabolism by epidermal growth factor. Eur J Biochem 197:805-13
Claro, E; Wallace, M A; Fain, J N et al. (1991) Altered phosphoinositide-specific phospholipase C and adenylyl cyclase in brain cortical membranes of cats with GM1 and GM2 gangliosidosis. Brain Res Mol Brain Res 11:265-71
Nair, B G; Steinke, L; Yu, Y M et al. (1991) Increase in the number of atrial natriuretic hormone receptors in regenerating rat liver. J Biol Chem 266:567-73
Nair, B G; Patel, T B (1991) Inhibition of hepatic adenylate cyclase by NADH. Life Sci 49:915-23

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