Sulfur‐substituted and α‐methylated fatty acids as peroxisome proliferator‐activated receptor activators

FA with varying chain lengths and an α‐methyl group and/or a sulfur in the β‐position were tested as peroxisome proliferator‐activated receptor (PPAR)α,‐δ(β), and‐γ ligands by transient transfection in COS‐1 cells using chimeric receptor expression plasmids, containing cDNAs encoding the ligand‐binding domain of PPARα,‐δ, and‐γ. For PPARα, an increasing activation was found with increasing chain length of the sulfur‐substituted FA up to C 14 ‐S acetic acid (tetradecylthioacetic acid=TTA). The derivatives were poor, and nonsignificant, activators of PPARδ. For PPARγ, activation increased with increasing chain length up to C 16 ‐S acetic acid. A methyl group was introduced in the α‐position of palmitic acid, TTA, EPA, DHA, cis9,trans11 CLA, and trans10,cis12 CLA. An increased activation of PPARα was obtained for the α‐methyl derivatives compared with the unmethylated FA. This increase also resulted in increased expression of the two PPARα target genes acyl‐CoA oxidase and liver FA‐binding protein for α‐methyl TTA, α‐methyl EPA, and α‐methyl DHA. Decreased or altered metabolism of these derivatives in the cells cannot be excluded. In conclusion, saturated FA with sulfur in the β‐position and increasing carbon chain length from C 9 −S acetic acid to C 14 −S acetic acid have increasing effects as activators of PPARα and‐γ in transfection assays. Furthermore, α‐methyl FA derivatives of a saturated natural FA (palmitic acid), a sulfur‐substituted FA (TTA), and PUFA (EPA, DHA, c 9, t 11 CLA, and t 10, c 12 CLA) are stronger PPARα activators than the unmethylated compounds.