Abstract
The mechanisms behind the hypotriglyceridemic effect of 1,10-bis(carboxymethylthio)decane (3-thiadicarboxylic acid) and tetradecylthioacetic acid and the development of fatty liver caused by 3-tetradecylthiopropionic acid (Aarsland et al. 1989. J. Lipid Res. 30: 1711-1718.) were studied in the rat. Repeated administration of S-substituted non-beta-oxidizable fatty acid analogues to normolipidemic rats resulted in a time-dependent decrease in plasma triglycerides, phospholipids, and free fatty acids. This was accompanied by an acute reduction in the liver content of triglycerides and an increase in the hepatic concentration of phospholipids. Mitochondrial fatty acid oxidation was stimulated, whereas lipogenesis was inhibited. The activity of phosphatidate phosphohydrolase decreased while the activity of CTP:phosphocholine cytidylyltransferase increased. These results suggest that the observed triglyceride-lowering effect was due to increased mitochondrial fatty acid oxidation accompanied by a reduction in the availability of the substrate i.e., free fatty acid, along with an enzymatic inhibition (phosphatidate phosphohydrolase). Administration of 3-tetradecylthiopropionic acid led to a drastic increase in the hepatic triglyceride content. Levels of plasma triglyceride phospholipid and free fatty acid also increased. Phosphatidate phosphohydrolase activity was stimulated whereas CTP:phosphocholine cytidylyltransferase was inhibited. Mitochondrial fatty acid oxidation was decreased. These data indicate that the development of fatty liver as an effect of 3-tetradecylpropionic acid is probably due to accelerated triglyceride biosynthesis, which is mediated by an increase in the availability of fatty acid along with stimulation of phosphatidate phosphohydrolase. The results of the present study speak strongly in favor of the hypothesis that phosphatidate phosphohydrolase is a major rate-limiting enzyme in triglyceride biosynthesis. Furthermore, they point out that the biosynthesis of triglycerides and phospholipids might be coordinately regulated. Such regulation is possibly mediated via phosphatidate phosphohydrolase and CTP:phosphocholine cytidylyltransferase. Whether the increase in hepatic phospholipids via increased CDP-pathway accounts for an increase of lipid components for proliferation of peroxisomes (3-thiadicarboxylic acid and tetradecylacetic acid) should be considered.
Highlights
The mechanisms behind the hypotriglyceridemic effect of 1,lO-bis(carboxymethy1thio)decane (3-thiadicarboxylic acid) and tetradecylthioacetic acid and the development of fatty liver caused by 3-tetradecylthiopropionicacid
In keeping with previous observations [4], plasma triglycerides, plasma cholesterol, and hepatic triglycerides were significantly lowered after administration of 3thiadicarboxylic acid and tetradecylthioacetic acid (Table 1).The hypolipidemic effect (Fig. 1)and reduced concentration of hepatic triglyceride (Fig. 2) were already established after 1-2 days
This study demonstrates that administration of 3-thiadicarboxylic and tetradecylthioacetic acids decreases the hepatic and plasma content of triglycerides, whereas induction of fatty liver and hyperlipidemia were observed with 3-tetradecylthiopropionic acid (Fig. 1 and Fig. 2)
Summary
The mechanisms behind the hypotriglyceridemic effect of 1,lO-bis(carboxymethy1thio)decane (3-thiadicarboxylic acid) and tetradecylthioacetic acid and the development of fatty liver caused by 3-tetradecylthiopropionicacid Repeated administration of S-substituted non-P-oxidizable fatty acid analogues to normolipidemic rats resulted in a timedependent decrease in plasma triglycerides, phospholipids, and free fatty acids. This was accompanied by an acute reduction in the liver content of triglycerides and an increase in the hepatic concentration of phospholipids. The mechanism by which these non-@oxidizable fatty acid analogues reduce plasma triglyceride levels is not fully elucidated Both the mitochondrial and peroxisomal &oxidation of fatty acids have been reported to be stimulated by these compounds [2], while lipogenesis and the incorporation of fatty acids into triglycerides were found to be decreased [3].
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