Abstract
Abstract The dietary regulation of fatty acid synthesis de novo in two transplantable hepatomas, 7777 and 9618A, has been studied by comparison of the acetyl coenzyme A carboxylase and fatty acid synthetase activities of tumor and host liver, both in animals fasted 48 hours and in those subsequently refed a fat-free diet for 48 hours. Neither acetyl-CoA carboxylase nor fatty acid synthetase of these hepatomas was subject to the changes in enzyme concentration normally observed in host liver following dietary alteration. Thus, in livers of refed animals acetyl-CoA carboxylase activity was 12- to 29-fold greater than in the livers of fasted animals. Neither tumor studied showed any change in enzyme levels upon refeeding 48-hour fasted animals; 1.4 mµmoles of malonyl-CoA were formed per mg per min for hepatoma 7777 and 3.3 mµmoles of malonyl-CoA were formed per mg per min for hepatoma 9618A. These activities of enzyme are 5- to 10-fold greater than fasting levels in host liver. Fatty acid synthetase levels in host livers increased 12- to 20-fold after refeeding. Again, neither tumor showed significant changes in enzyme activity upon refeeding fasted animals. Both acetyl-CoA carboxylase and fatty acid synthetase from hepatoma were inhibited by palmityl-CoA despite their lack of response to dietary alteration. Acetyl-CoA carboxylase was purified 164-fold from rat liver and 67-fold from hepatoma 7777 to define further this lack of regulation. Studies of the purified enzymes disclosed that the tumor enzyme was essentially identical with that derived from liver in terms of heat inactivation, affinities for acetyl-CoA and ATP, activation and aggregation by citrate, product inhibition by malonyl-CoA, pH optima, and intrinsic specific activity as determined from biotin content. These experiments suggest that the acetyl-CoA carboxylase from the tumors is the same enzyme as that from host liver, and that the increased activity in the tumors is due to an increased amount of enzyme rather than a structurally altered enzyme.
Highlights
Neither tumor showed significant changes in enzyme activity upon refeeding fasted animals. Both acetyl-CoA carboxylase and fatty acid synthetase from hepatoma were inhibited by pahnityl-CoA despite their lack of response to dietary alteration
The dietary regulation of fatty acid synthesis de novo was investigated in two transplantable hepatomas, 96184 which is a highly differentiated and very slowly growing hepatoma (7 months average generation time) and 7777 which is less differentiated and rapidly growing (1.5 months average generation time)
Previous studies of the regulation of cholesterol biosynthesis in 14 different transplantable rat hepatomas have indicated a loss of the normal inhibition of this pathway by dietary cholesterol
Summary
34) and 9618A (Generation 3) from male Buffalo strain rats were used in these studies. Tumor cells were inoculated intramuscularly into both hind legs and the rats were shipped by air to St. Louis shortly after tumor implantation. Animals were fed Purina chow until the tumors reached a size of 0.5 to 1.5 cm in diameter and were transferred to individual cages for the various dietary experiments. In preliminary experiments it was shown that acetyl-CoA carboxylase and fatty acid synthetase activit,y in liver rise progressively after refeeding fasted animals, reaching a peak by 48 hours and remaining at this level thereafter. 48 hours of refeeding were used in the dietary experiments
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