Fatty acids and retinoids regulate lipid metabolism by activating peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) heterodimers. PPARs, including PPARα, β, and γ, control peroxisomal β-oxidation of fatty acids by inducing the acyl-CoA oxidase gene, which encodes the rate-limiting enzyme in this pathway. PPARα forms a heterodimer with RXRβ, and together they activate the acyl-CoA oxidase gene promoter. Natural fatty acids, especially polyunsaturated fatty acids (PUFAs), activate PPARs as effectively as the hypolipidemic drug Wy 14,643, the most potent known activator. A synthetic arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (ETYA), is 100 times more effective than Wy 14,643 in activating PPARα. These findings demonstrate that PPAR and RXR signaling pathways converge in the regulation of peroxisomal β-oxidation of fatty acids by fatty acids and retinoids. The study also shows that fatty acids, including PUFAs, activate PPARα, and that ETYA is a potent activator of xPPARα. The results highlight the importance of PPARs in lipid metabolism and suggest that PUFAs may have a positive feedback effect on peroxisomal β-oxidation, contributing to their hypolipidemic effects. The study provides insights into the molecular mechanisms underlying the regulation of lipid metabolism by fatty acids and retinoids.Fatty acids and retinoids regulate lipid metabolism by activating peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) heterodimers. PPARs, including PPARα, β, and γ, control peroxisomal β-oxidation of fatty acids by inducing the acyl-CoA oxidase gene, which encodes the rate-limiting enzyme in this pathway. PPARα forms a heterodimer with RXRβ, and together they activate the acyl-CoA oxidase gene promoter. Natural fatty acids, especially polyunsaturated fatty acids (PUFAs), activate PPARs as effectively as the hypolipidemic drug Wy 14,643, the most potent known activator. A synthetic arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (ETYA), is 100 times more effective than Wy 14,643 in activating PPARα. These findings demonstrate that PPAR and RXR signaling pathways converge in the regulation of peroxisomal β-oxidation of fatty acids by fatty acids and retinoids. The study also shows that fatty acids, including PUFAs, activate PPARα, and that ETYA is a potent activator of xPPARα. The results highlight the importance of PPARs in lipid metabolism and suggest that PUFAs may have a positive feedback effect on peroxisomal β-oxidation, contributing to their hypolipidemic effects. The study provides insights into the molecular mechanisms underlying the regulation of lipid metabolism by fatty acids and retinoids.