THIA FATTY-ACIDS, METABOLISM AND METABOLIC EFFECTS

(1) The chemical properties of thia fatty acids are similar to normal fatty acids, but their metabolism (see below: points 2-6) and metaboli c effects (see below: points 7-15) differ greatly from these and are d ependent upon the position of the sulfur atom. (2) Long-chain thia fat ty acids and alkylthioacrylic acids are activated to their CoA esters in endoplasmatic reticulum. (3) 3-Thia fatty acids cannot be beta-oxid ized. They are metabolized by extramitochondrial omega-oxidation and s ulfur oxidation in the endoplasmatic reticulum followed by peroxisomal beta-oxidation to short sulfoxy dicarboxylic acids.(4) 4-Thia fatty a cids are beta-oxidized mainly in mitochondria to alkylthioacryloyl-CoA esters which accumulate and are slowly converted to 2-hydroxy-4-thia acyl-CoA which splits spontaneously to an alkylthiol and malonic acid semialdehyde-CoA ester. The latter presumably is hydrolyzed and metabo lized to acetyl-CoA and CO2. (5) Both 3- and 4-thiastearic acid are de saturated to the corresponding thia oleic acids. (6) Long-chain 3- and 4-thia fatty acids are incorporated into phospholipids in vivo, parti cularly in heart, and in hepatocytes and other cells in culture. (7) L ong-chain 3-thia fatty acids change the fatty acid composition of the phospholipids; in heart, the content of n - 3 fatty acids increases an d n - 6 fatty acids decreases. (8) 3-Thia fatty acids increase fatty a cid oxidation in liver through inhibition of malonyl-CoA synthesis, ac tivation of CPT I, and induction of CPT-II and enzymes of peroxisomal beta-oxidation. Activation of fatty acid oxidation is the key to the h ypolipidemic effect of 3-thia fatty acids. Also other lipid metabolizi ng enzymes are induced. (9) Fatty acid- and cholesterol synthesis is i nhibited in hepatocytes. (10) The nuclear receptors PPAR alpha and RXR alpha are induced by 3-thia fatty acids. (11) The induction of enzyme s and of PPAR alpha and RXR alpha are increased by dexamethasone and c ounteracted by insulin. (12) 4-Thia fatty acids inhibit fatty acid oxi dation and induce fatty liver in vivo. The inhibition presumably is ex plained by accumulation of alkylthioacryloyl-CoA in the mitochondria. This metabolite is a strong inhibitor of CPT-II.(13) Alkylthioacrylic acids inhibits both fatty acid oxidation and esterification. Inhibitio n of esterification presumably follows accumulation of extramitochondr ial alkylthioacryloyl-CoA, an inhibitor of microsomal glycerophosphate acyltransferase. (14) 9-Thia stearate is a strong inhibitor of the De lta(9)-desaturase in liver and 10-thia stearate of dihydrosterculic ac id synthesis in trypanosomes. (15) Some attempts to develop thia fatty acids as drugs are also reviewed.