In this project we will extend our previous studies defining factors controlling hepatic triglyceride (TG) metabolism under normal conditions to the situation following severe burn injury. We will investigate the general hypothesis that hepatic fatty acid oxidation is inhibited following burn injury. Related to that general hypothesis, we propose to investigate the following specific hypotheses with regard to the response to burn injury: 1. Hepatic fatty acid oxidation is limited in burn injury by an inhibition of carnitine palmitoyltransferase-I (CPT-I). 2. CPT-I is inhibited by a high concentration of hepatic malonyl-CoA. Further, we propose that the high concentration of malonyl-CoA stems from accelerated glucose metabolism and production of pyruvate. 3. Hepatic uptake of plasma free fatty acids (FFA) is a direct function of delivery and thus not limited by an inhibition of oxidation. Rather, when oxidation is limited, plasma FFA are channeled preferentially into hepatic triglycerides. 4. Changes in FFA availability have a greater effect on hepatic TG synthesis in burn injury than normal because the low activity of CPT-I limits the extent to which fatty acid oxidation can respond to changes in availability. 5. Carbohydrate intake causes a greater hepatic uptake of glucose in burn injury than normal because of hyperglycemia. As a consequence, the de novo synthesis of fatty acids in the liver is stimulated to a greater extent than normal because of the activated state of acetyl-CoA carboxylase (ACC). 6. Maintenance of euglycemia during glucose intake by means of infusion will decrease the proportionate uptake of glucose by the liver, and thereby reduce the rate of fatty acid synthesis. Studies will be performed in patients with severe burns and in normal volunteers. Arterial and hepatic vein catheters will enable calculation of the splanchnic balance of substrates and metabolites labeled with a combination of stable and radioactive isotopes. Corresponding studies will be performed in normal and burned pigs in order to examine in greater depth the mechanisms responsible for the observed responses in human patients. Taken together, these results will help to explain the metabolic basis for abnormal hepatic fatty acid and triglyceride metabolism in stress and insulin-resistant states such as burn injury. This information will provide a physiological basis for the development of a practical approach to controlling increased triglyceride synthesis in insulin resistant states.
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