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 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.
Skrede
S
S
Institute of Medical Biochemistry, University of Oslo, Norway.
Sørensen
H N
HN
Larsen
L N
LN
Steineger
H H
HH
Høvik
K
K
Spydevold
O S
OS
Horn
R
R
Bremer
J
J
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase; D013379:Substrate Specificity; D013455:Sulfur / Q000737:chemistry; D014280:Triglycerides / Q000378:metabolism
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D010743:Phospholipids; D014280:Triglycerides; D013455:Sulfur; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase; D042962:Acyl-CoA Oxidase; D044942:Acyl-CoA Dehydrogenase, Long-Chain