Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways.
Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase. Transfection assays in hepatoma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediated by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting amounts of retinoid X receptor (RXR) required for PPAR activation. Increasing amounts of RXR partially reversed the inhibition in a reciprocal manner; PPAR also inhibited TR activation. Results with heterodimerization-deficient TR and PPAR mutants further confirmed that interaction between PPAR and TR signaling systems is indirect. These results suggest that a convergence of the peroxisome proliferator and T3 signaling pathways occurs through their common interaction with the heterodimeric partner RXR.
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
R
R
Chu
L D
LD
Madison
Y
Y
Lin
P
P
Kopp
M S
MS
Rao
J L
JL
Jameson
J K
JK
Reddy
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis; D000818:Animals; D001483:Base Sequence; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis; D058607:Fibric Acids; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007535:Isomerases / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000096:biosynthesis; D009154:Mutation; D010084:Oxidation-Reduction; D063994:Peroxisomal Bifunctional Enzyme; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000494:pharmacology*
D058607:Fibric Acids; D009097:Multienzyme Complexes; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014284:Triiodothyronine; D002995:Clofibric Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; C576253:EHHADH protein, human; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases; C019304:ciprofibrate