Introduction

Thia fatty acids are fatty acid analogues where a methyl group of a normal fatty acid is substituted with sulphur. Such fatty acids can be categorised in two groups with distinct biological and metabolic properties depending on the position of the sulphur-atom in the fatty acid. In 3-thia fatty acids the P-methyl group is substituted with sulphur and, hence, they are blocked and cannot undergo p-oxidation. As they are substrates for CPT-I and CPT-II they can enter the mitochondria and further metabolism is blocked because they are not substrates for acyl-CoA-dehydrogenase. The only method of metabolising the 3-thia fatty acids is, consequently, («-oxidation to a dicarboxylic acid, followed by P-oxidation from the co-end.

The 3-thia, non-p-oxidable thia fatty acids (as exemplified by TTA (tetradecylth-ioacetic acid, HOOC-CH2-S-CH2(13)-CH3) decrease plasma triglycerides and cholesterol levels when administered to rats.1 At the same time TTA increased the hepatic fatty acid oxidation capacities. Recently we have demonstrated that stimulation of mitochondrial P-oxidation, but not peroxisomal fatty acid oxidation, decreases hepatic triglyceride formation.2 This has also been shown with co-3 fatty acids and fibrates in different animal models (rats, rabbits and dogs). Altogether the mitochondrion seems to be the principal target for the plasma triglycerid lowering effect.

The other category of thia-fatty acids is the p-oxidable variant with sulphur in the 4th position as exemplified by TTP (tetradecylthiopropanoic acid, HOOC-CH2-CH2-S-CH2(13)-CH3). Since the P-carbon is available for oxidation, these fatty acid analogues can undergo one cycle of mitochondrial p-oxidation, but the alkyl-thioacryloyl-CoAs then formed are poor substrates for both mitochondrial hydratase3 and for CPT-II. Consequently they will accumulate in the mitochondrial matrix where they inhibit normal fatty acid oxidation.4 In contrast to the effect obtained with TTA, repeated

Table 1. List of thia fatty acids.

Compound

Formula

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