COORDINATE INDUCTION OF HEPATIC FATTY ACYL-COA OXIDASE AND P4504A1 INRAT AFTER ACTIVATION OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) BY SULFUR-SUBSTITUTED FATTY-ACID ANALOGS

1. In the liver of rat fed a single dose of 3-thia fatty acids, 3-dith iahexadecanedioic acid (3-thiadicarboxylic acid) and tetradecylthioace tic acid, steady-state levels of P45041 and fatty acyl-CoA oxidase mRN As increased in parallel. The increases were significant 8 h after adm inistration, reaching a maximum after 12 h and decreased from 12 to 24 h after administration. 2. The corresponding enzyme activities of P45 04A1 and fatty acyl-CoA oxidase were also induced in a parallel manner by the 3-thia fatty acids. The enzyme activities were significantly i ncreased 12 h after administration and increased further after 24 h. T his may reflect a possible effect of the 3-thia fatty acids not only o n mRNA levels, but also on the translation and degradation rate of the two enzymes. 3. Repeated administration of 3-thia fatty acids resulte d in an increase of the specific P4504A1 protein accompanied with an i ncreased lauric acid hydroxylase activity. The correlation between ind uction of P4504A1 and fatty acyl-CoA oxidase mRNAs and their enzyme ac tivities may reflect a coordinated rather than a causative induction m echanism, and that these genes respond to a common signal. This sugges ts that the increased P450 activity may not be responsible or be a pre requisite for fatty acyl-CoA oxidase induction. 4. Since the peroxisom e proliferator-activated receptor (PPAR) plays a role in mediating the induction of fatty acyl-CoA oxidase, we analysed the activation of PP AR by fatty acids and sulphur-substituted analogues utilizing a chimer a between the N-terminal and DNA-binding domain of the glucocorticoid receptor and the putative ligand-binding domain of PPAR. Arachidonic a cid activated this chimeric receptor in Chinese hamster ovary cells. I nhibitors of P450 did not affect the activation of PPAR by arachidonic acid. Furthermore, dicarboxylic acids including 1,12-dodecanedioic ac id or 1,16-hexadecanedioic acid only weakly activated the chimera. 3-T hiadicarboxylic acid, however, was a much more effective activator tha n the non-sulphur-substituted analogues. In conclusion, the data sugge st that the most likely mechanism of the induction process is fatty ac id-induced activation of PPAR, which then leads to a coordinated induc tion of P4504A1 and fatty acyl-CoA oxidase.