The continuing objectives of the proposed research are to describe and understand the biochemical and physiological mechanisms which regulate the metabolism of free fatty acids (FFA) by the liver. We propose to study the interrelationships among secretion oftriglyceride and the very low density lipoprotein (VLDL), oxidation of FFA (ketogenesis and CO2 production), lipogenesis and glycerolipid synthesis, cholesterogenesis, and hepatic steatosis. The perfused rat liver and isolated hepatocytes will be used to study alternate pathways of metabolism of FFA by the liver. These studies in vitro will be correlated with VLDL triglyceride secretion rate and estimation of VLDL utilization in the intact animal. We will continue to investigate the endocrine-dependent regulation of hepatic secretion, composition, and properties of the VLDL, and related alternate pathways of metabolism of FFA. The effect of thyroidal status, adrenoglucocorticoids, gonadal steroids, glucagon, catecholamines, and cyclic nucleotides will be studied. We plan to investigate the role of calcium (Ca++) ion as a regulator of the microsomal synthesis of glycerolipids and as a possible mediator of hormal action in hepatic lipid metabolism. We plan to continue to study the substrate (FFA)-dependent regulation of hepatic secretion, composition, and properties of the VLDL. We will continue to investigate how the various properties of a specific VLDL secreted by the liver in vitro in response to a specific FFA or mixture, affect the subsequent extra-hepatic utilization of that VLDL. Utilization will be evaluated by activity of lipoprotein lipase in vitro, and by measurement of plasma half-life (T1/2) in vivo. We will studdy the interrelationships among regulation of output the VLDL and cholesterogenesis and cholesterol esterification (activation of HMG-CoA reductase and LCAT, respectively). The effects of diet, endocrinopathies and disease on plasma lipoproteins must, in part, result from altered metabolism of FFA by the liver. Understanding of these mechanisms is the purpose of this study.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027850-09
Application #
3339369
Study Section
Metabolism Study Section (MET)
Project Start
1984-01-01
Project End
1990-06-30
Budget Start
1988-12-01
Budget End
1990-06-30
Support Year
9
Fiscal Year
1989
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
Stone, W L; Heimberg, M; Scott, R L et al. (1994) Altered hepatic catabolism of low-density lipoprotein subjected to lipid peroxidation in vitro. Biochem J 297 ( Pt 3):573-9
Fungwe, T V; Cagen, L M; Wilcox, H G et al. (1994) Effects of dietary cholesterol on hepatic metabolism of free fatty acid and secretion of VLDL in the hamster. Biochem Biophys Res Commun 200:1505-11
Fungwe, T V; Fox, J E; Cagen, L M et al. (1994) Stimulation of fatty acid biosynthesis by dietary cholesterol and of cholesterol synthesis by dietary fatty acid. J Lipid Res 35:311-8
Fungwe, T V; Cagen, L M; Cook, G A et al. (1993) Dietary cholesterol stimulates hepatic biosynthesis of triglyceride and reduces oxidation of fatty acids in the rat. J Lipid Res 34:933-41
Olubadewo, J O; Heimberg, M (1993) Effects of adrenergic agonists and antagonists on the metabolism of [1-14C]oleic acid by rat hepatocytes. Biochem Pharmacol 45:2441-7
Elam, M B; Wilcox, H G; Solomon, S S et al. (1992) In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver. Endocrinology 131:2717-22
Fungwe, T V; Cagen, L; Wilcox, H G et al. (1992) Regulation of hepatic secretion of very low density lipoprotein by dietary cholesterol. J Lipid Res 33:179-91
Cagen, L M; Fungwe, T V; Wilcox, H G et al. (1992) Biphasic effect of oleic acid on hepatic cholesterogenesis. Biochem Biophys Res Commun 183:21-6
Scott, R L; Kheshti, A; Heimberg, M et al. (1991) The role of selenium in the secretion of very-low-density lipoprotein in the isolated perfused rat liver. Biochem J 279 ( Pt 3):741-5
Castellani, L W; Wilcox, H C; Heimberg, M (1991) Relationships between fatty acid synthesis and lipid secretion in the isolated perfused rat liver: effects of hyperthyroidism, glucose and oleate. Biochim Biophys Acta 1086:197-208

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