The regulation of hepatic fatty acid oxidation is important from a medical standpoint several reasons. First, the rate of hepatic fatty acid oxidation is known to be extremely important for determining what fraction of the fatty acid received by the liver is packaged into very low density lipoprotein (VLDL) particles, and thus regulation of fatty acid oxidation is important for understanding mechanism regulating the hepatic production of lipoproteins and also their involvement in the process of atherosclersis. Second, when hepatic fatty acid oxidation is uncontrolled, as in diabetes mellitus Type I, ketoacidosis develops. In addition, it is known that various disorders of lipid metabolism result from altered thyroid status including alterations in hepatic fatty acid oxidation. The primary site for physiological inhibitor, malonyl-CoA. Previous work in this laboratory has shown that the activity of carnitive palmitoyltransfearse and its sensitivity to inhibition by malonyl- CoA change during fasting, diabetes, and in both hyperthyroid and hypothyroid states. Insulin and thyroid hormone are clearly involved in the regulatory mechanism for hepatic fatty acid oxidation. The long-term objective of this project is to understand the mechanisms by which hormones exert their control over camitine palmitoyltransferase.
The specific aims are: (a) to establish whether the recently discovered carnitive palmitoyltransferase of the mitochondrial outer membrane is important in the regulation of hepatic fatty acid oxidation; (b) to establish the mechanism by which the ki of carnitive palmitoyltransferase for malonyl-CoA is altered in various physiological and pathophysiological states; (c) to ascertain what mechanisms are involved in the control of carnitive palmitoyltransferase activity by insulin and thyroid hormone; (d) to determine whether additional hormonal control mechanisms exist for regulation hepatic fatty acid oxidation through changes in carnitive palmitoyltransferase or modification of other hormonal signals; (e) to isolate, purify, characterize, and produce antibodies to the inner carnitive palmitoyltransferase; and (g) to examine the effects of fasting, refeeding, insulin and thyroid hormone on the synthesis of carnitive palmitoyltransferase messenger RNA's These objectives will be achieved by conducting experiments in vivo and in vitro using normal rats, isolated rat hepatocytes, cultured hepatocytes, isolated rat liver mitochondria isolated mitochondrial outer membranes, and isolated, purified carnitive palmitoyltransferase. These studies, performed at organizational levels ranging from the intact animal level down to the molecular level, will contribute greatly to our understanding of the regulation of hepatic fatty acid oxidation and its integration into the control of hepatic lipid and lipoprotein metabolism.
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