3- Thia fatty acids peroxisome proliferation

TTA is a fatty acid analogue in which a sulfur atom replaces the P-mehylene groups in the alkyl-chain (a 3-thia fatty acid). TTA, therefore, cannot be P-oxidized. Paradoxically, TTA is both mitochondrial and peroxisomal proliferator and the hepatic mitochondrial and peroxisomal fatty acid oxidation capacities are increased (Table 2). In addition to its biochemical and morphological effects, TTA decrease serum TG (Table 1) very low density lipoprotein (VLDL)-TG, cholesterol and free fatty acid (NEFA) levels in rats. Thus, the observed reduction in plasma TG levels during TTA administration could be accomplished by retarded synthesis, reduced hepatic output, enhanced clearance or a combination of these factors. 3-Thia fatty acid resulted in a slight inhibition in the activities of ATP-citrate lyase and fatty acid synthase. However, the impact of... 

When the synthesis of lipids is reduced due to the presence of fatty acid analogs, the NEFAs will be diverted from the esterification pathway. The level of NEFAs in the hepatocytes treated with 3-thia fatty acids tended to decrease. This indicates that the mitochondrial P-oxidation was increased, as the peroxisomal P-oxidation was unchanged in these hepatocytes. Thus, it is likely that the non-P-oxidizable fatty acid analogs reduced the availability of fatty acids for TG-synthesis due to increased mitochondrial fatty oxidation. The lack of effect on the peroxisomal P-oxidation confirms the in vivo data that the hypotriglyceridemic effect of the analogs can be dissociated from the proliferation of peroxisomes." ... 

Thia fatty acids have been used as tools in experimental models to further penetrate the mechanisms of the lipid metabolism. These fatty acids are activated to their respective CoA-esters, but, they cannot be degraded by 3-oxidation because of the sulfur substitution in 3-position (reviewed ). Tetradecylthioacetic acid (TTA), a representative member of the 3-thia family, has the chemical structure of palmitic acid (C16) in which a sulfur atom is located between the 2 and 3-carbon atoms (COOH-CH2-S-(CH2)i3-CH3). TTA is a novel hypolipidemic drug which has been shown to combine several effects of CO-3 PUFAs, such as EPA, and structurally unrelated peroxisome proliferators, such as phenylacetate and fibrates. From this perspective we wanted to investigate if TTA shares the antitumor activity found for these functionally related compounds, and furthermore to study the metabolic effects of TTA in cancer cells in relation to the effects found in hepatocytes. 

Beige, R.K., Aarsland, A., Kryvi, H., Bremer, A. Aarsaether, N. 1989 Biochim. Biophys. Acta 1004 345-356. Alkylthioacetic acids (3-thia fatty acids)-A new group of non-ph-oxidizable peroxisome-inducing fatty acid analogues. . A study on the structural requirements for proliferation of peroxisome s and mitochondria in rat lliver. 

Both EPA and C14-S-acetic acid are converted to their respective CoA esters in mitochondria. Furthermore, in contrast to DHA-CoA, EPA-CoA and C14-S-acetyl-CoA are easily transferred into the mitochondria by the CAT system. EPA is more difficult to oxidize than saturated and monounsaturated fatty acids, due to the double bonds and C14-S-acetic acid is non-oxidizable by P-oxidation,due to the sulfur atom in 3-position. Thus, accumulation of their respective CoA esters in the mitochondria might give an fatty acid overload signal leading to inaeased mitochondrial fatty acid oxidation. C14-S-acetic acid mimics the effects of peroxisome proliferators such as the fibrates and it was recently shown that it may be a ligand for the peroxisome proliferating activated receptor (PPAR) a. As administration of the 3-thia fatty acids seem to force EPA to the mitochondria, an additional fish oil effect might be seen. 

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