ACUTE MODULATION OF RAT HEPATIC LIPID-METABOLISM BY SULFUR-SUBSTITUTED FATTY-ACID ANALOGS

A single oral dose of two 3-thia (3-thiadicarboxylic and tetradecylthi oacetic acids) and of 4-thia (tetradecylthiopropionic acid) fatty acid s were administered to normolipidemic rats and their effects on lipid metabolism over a 24 hr period were, studied. All three thia fatty aci ds could be detected in plasma 2 hr after treatment. Tetradecylthioace tic and tetradecylthiopropionic acids were detected in different hepat ic lipid fractions but were incorporated mainly into hepatic phospholi pids. Two hours after administration hepatic mitochondrial beta-oxidat ion and the total liver level of long-chain fatty acyl-CoA increased w ith a concomitant decrease in saturated fatty acids, total hepatic mal onyl-CoA and plasma triacylglycerol levels in the 3-thia fatty acid gr oups. Tetradecylthiopropionic acid administration caused a decrease in mitochondrial beta-oxidation and an increase in plasma triacylglycero l at 24 hr. The activities of key lipogenic enzymes were unaffected in all treatment groups. Plasma cholesterol level was reduced only at 8 hr in 3-thiadicarboxylic acid treated rats although 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reductase was suppressed already at 2, 4, 8 and 12 hr. The results show that thia fatty acids are rapidly absorbed an d are systemically available after oral administration but the 3-thia fatty acids reached systemic circulation more slowly and less complete ly than the 4-thia fatty acid. Very low levels of the thia fatty acids are detected in plasma 24 hr after a single administration. They are incorporated into all hepatic lipid classes, especially phospholipids. Rapid incorporation of a non beta-oxidizable thia fatty acid into hep atic lipids may cause a diversion of other fatty acids from glycerolip id biosynthesis to mitochondrial beta-oxidation. Stimulation of mitoch ondrial beta-oxidation and suppression of HMG-CoA reductase are primar y events, occurring within hours, after 3-thia fatty acid administrati on. The hypotriglyceridemic effect of the 3-thia fatty acids observed at 2-3 hr is independent of the activities of key lipogenic and triacy lglycerol synthesising enzymes.