HEPATIC FATTY-ACID METABOLISM AS A DETERMINANT OF PLASMA AND LIVER TRIACYLGLYCEROL LEVELS - STUDIES ON TETRADECYLTHIOACETIC AND TETRADECYLTHIOPROPIONIC ACIDS

To investigate the importance of factors influencing substrate availab ility for triacylglycerol biosynthesis on lipoprotein metabolism, the effects of two opposite acting sulphur-substituted fatty acid analogue s, tetradecylthioacetic acid and tetradecylthiopropionic acid were stu died. Administration of tetradecylthioacetic acid to rats resulted in a reduction of plasma levels of triacylglycerols (44%) and cholesterol (26%). This was accompanied by a reduction in very-low-density lipopr otein (VLDL) triacylglycerols (48%), VLDL cholesterol (36%), low-densi ty lipoprotein (LDL) cholesterol (36%) and high-density lipoprotein (H DL) triacylglycerols (50%), whereas HDL cholesterol levels did not cha nge. Subsequently, the HDL/LDL-cholesterol ratio increased by 40%. The cholesterol-lowering effect was accompanied by a reduction in hydroxy methylglutaryl CoA (HMG-CoA) reductase activity (37%). Both mitochondr ial and peroxisomal fatty acid oxidation increased (1.7 fold and 5.3-f old, respectively). Furthermore, there was a significant negative corr elation between plasma triacylglycerols and mitochondrial fatty acid o xidation. Hepatic triacylglycerol synthesis was retarded, as indicated by a decrease in VLDL triacylglycerol secretion (40%), and by a reduc ed liver triacylglycerol content (29%). The activities of lipoprotein lipase and hepatic lipase in post-heparin plasma were not affected. Mi crosomal and cytosolic phosphatidate phosphohydrolase activities were inhibited (28% and 70%, respectively). Hepatic malonyl-CoA levels decr eased by 29% and the total activity of acetyl-CoA carboxylase was redu ced (23%). In hepatocytes treated with tetradecylthioacetic acid, mito chondrial fatty acid oxidation increased markedly (100%) and triacylgl ycerol secretion was reduced (40%). In tetradecylthiopropionic-acid-tr eated rats, a significant increase in both plasma and VLDL triacylglyc erols was found (46% and 72%, respectively) but VLDL triacylglycerol s ecretion was unaffected. However, no effect on either plasma or lipopr otein cholesterol levels was seen. Mitochondrial fatty acid oxidation was decreased by 50% and hepatic triacylglycerol levels increased by 3 3%. In hepatocytes exposed to tetradecylthiopropionic acid, triacylgly cerol synthesis increased (100%) while triacylglycerol secretion and f atty acid oxidation remained unaltered. The results illustrate that li poprotein triacylglycerol levels can be modulated by changes in the av ailability of fatty acid substrate for triacylgIycerol biosynthesis, m ainly by affecting mitochondrial fatty acid oxidation. In addition, we demonstrate that suppression of rat hepatic HMG-CoA reductase activit y during treatment with tetradecylthioacetic acid may contribute to a cholesterol-lowering effect.