THYROID-HORMONE (T-3) INHIBITS CIPROFIBRATE-INDUCED TRANSCRIPTION OF GENES ENCODING BETA-OXIDATION ENZYMES - CROSS-TALK BETWEEN PEROXISOME PROLIFERATOR AND T-3 SIGNALING PATHWAYS

Peroxisome proliferators cause rapid and coordinated transcriptional a ctivation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isofor m(s). Since the thyroid hormone (T-3; 3,3',5-triiodothyronine) recepto r (TR), another member of the nuclear hormone receptor superfamily, re gulates a subset of fatty acid metabolism genes shared with PPAR, we e xamined the possibility of interplay between peroxisome proliferator a nd T-3 Signaling pathways. T-3 inhibited ciprofibrate-induced lucifera se activity as well as the endogenous peroxisomal beta-oxidation enzym es in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene f used to the coding region of luciferase. Transfection assays in hepato ma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediate d by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting a mounts of retinoid X receptor (RXR) required for PPAR activation. Incr easing amounts of RXR partially reversed the inhibition in a reciproca l manner; PPAR also inhibited TR activation. Results with heterodimeri zation-deficient TR and PPAR mutants further confirmed that interactio n between PPAR and TR signaling systems is indirect. These results sug gest that a convergence of the peroxisome proliferator and T-3 signali ng pathways occurs through their common interaction with the heterodim eric partner RXR.