Skrede S, Sørensen H N, Larsen L N, Steineger H H, Høvik K, Spydevold O S, Horn R, Bremer J
Institute of Medical Biochemistry, University of Oslo, Norway.
Biochim Biophys Acta. 1997 Jan 21;1344(2):115-31. doi: 10.1016/s0005-2760(96)00138-5.
(1) The chemical properties of thia fatty acids are similar to normal fatty acids, but their metabolism (see below: points 2-6) and metabolic effects (see below: points 7-15) differ greatly from these and are dependent upon the position of the sulfur atom. (2) Long-chain thia fatty acids and alkylthioacrylic acids are activated to their CoA esters in endoplasmatic reticulum. (3) 3-Thia fatty acids cannot be beta-oxidized. They are metabolized by extramitochondrial omega-oxidation and sulfur oxidation in the endoplasmatic reticulum followed by peroxisomal beta-oxidation to short sulfoxy dicarboxylic acids. (4) 4-Thia fatty acids 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 metabolized to acetyl-CoA and CO2. (5) Both 3- and 4-thiastearic acid are desaturated to the corresponding thia oleic acids. (6) Long-chain 3- and 4-thia fatty acids are incorporated into phospholipids in vivo, particularly in heart, and in hepatocytes and other cells in culture. (7) Long-chain 3-thia fatty acids change the fatty acid composition of the phospholipids: in heart, the content of n-3 fatty acids increases and n-6 fatty acids decreases. (8) 3-Thia fatty acids increase fatty acid oxidation in liver through inhibition of malonyl-CoA synthesis, activation of CPT I, and induction of CPT-II and enzymes of peroxisomal beta-oxidation. Activation of fatty acid oxidation is the key to the hypolipidemic effect of 3-thia fatty acids. Also other lipid metabolizing enzymes are induced. (9) Fatty acid- and cholesterol synthesis is inhibited in hepatocytes. (10) The nuclear receptors PPAR alpha and RXR alpha are induced by 3-thia fatty acids. (11) The induction of enzymes and of PPAR alpha and RXR alpha are increased by dexamethasone and counteracted by insulin. (12) 4-Thia fatty acids inhibit fatty acid oxidation and induce fatty liver in vivo. The inhibition presumably is explained 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. Inhibition of esterification presumably follows accumulation of extramitochondrial alkylthioacryloyl-CoA, an inhibitor of microsomal glycerophosphate acyltransferase. (14) 9-Thia stearate is a strong inhibitor of the delta 9-desaturase in liver and 10-thia stearate of dihydrosterculic acid synthesis in trypanosomes. (15) Some attempts to develop thia fatty acids as drugs are also reviewed.
(1) 硫代脂肪酸的化学性质与正常脂肪酸相似，但其代谢过程（见下文第2 - 6点）和代谢效应（见下文第7 - 15点）与正常脂肪酸有很大不同，且取决于硫原子的位置。(2) 长链硫代脂肪酸和烷硫基丙烯酸在内质网中被激活为它们的辅酶A酯。(3) 3 - 硫代脂肪酸不能进行β - 氧化。它们通过内质网中的线粒体外ω - 氧化和硫氧化，随后在过氧化物酶体中进行β - 氧化代谢为短链磺氧基二羧酸。(4) 4 - 硫代脂肪酸主要在线粒体中进行β - 氧化生成烷硫基丙烯酰辅酶A酯，该酯会积累并缓慢转化为2 - 羟基 - 4 - 硫代酰基辅酶A，后者会自发分解为烷硫醇和丙二酸半醛辅酶A酯。后者可能会被水解并代谢为乙酰辅酶A和二氧化碳。(5) 3 - 和4 - 硫代硬脂酸都会去饱和生成相应的硫代油酸。(6) 长链3 - 和4 - 硫代脂肪酸在体内会被整合到磷脂中，特别是在心脏中，以及在培养的肝细胞和其他细胞中。(7) 长链3 - 硫代脂肪酸会改变磷脂的脂肪酸组成：在心脏中，n - 3脂肪酸含量增加而n - 6脂肪酸含量减少。(8) 3 - 硫代脂肪酸通过抑制丙二酰辅酶A合成、激活肉碱棕榈酰转移酶I（CPT I）以及诱导肉碱棕榈酰转移酶II（CPT - II）和过氧化物酶体β - 氧化酶来增加肝脏中的脂肪酸氧化。脂肪酸氧化的激活是3 - 硫代脂肪酸降血脂作用的关键。其他脂质代谢酶也会被诱导。(9) 肝细胞中的脂肪酸和胆固醇合成受到抑制。(10) 3 - 硫代脂肪酸会诱导核受体过氧化物酶体增殖物激活受体α（PPARα）和视黄醇X受体α（RXRα）。(11) 地塞米松会增强酶以及PPARα和RXRα的诱导作用，而胰岛素则会起到拮抗作用。(12) 4 - 硫代脂肪酸在体内会抑制脂肪酸氧化并诱导脂肪肝。这种抑制作用可能是由于线粒体中烷硫基丙烯酰辅酶A的积累所致。这种代谢产物是CPT - II的强抑制剂。(13) 烷硫基丙烯酸既抑制脂肪酸氧化又抑制酯化作用。酯化作用的抑制可能是由于线粒体外烷硫基丙烯酰辅酶A的积累，它是微粒体甘油磷酸酰基转移酶的抑制剂。(14) 9 - 硫代硬脂酸是肝脏中Δ9 - 去饱和酶的强抑制剂，而10 - 硫代硬脂酸是锥虫中二氢硬脂酸合成的抑制剂。(15) 本文还综述了一些将硫代脂肪酸开发为药物的尝试。
