Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways.

Abstract

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.

• Authors: R Chu, L D Madison, Y Lin, P Kopp, M S Rao, J L Jameson, J K Reddy
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 25 Pg. 11593-7 (Dec 05 1995) ISSN: 0027-8424 [Print] United States
• PMID: 8524810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fibric Acids
• Multienzyme Complexes
• Receptors, Cytoplasmic and Nuclear
• Receptors, Retinoic Acid
• Receptors, Thyroid Hormone
• Recombinant Fusion Proteins
• Retinoid X Receptors
• Transcription Factors
• Triiodothyronine
• Clofibric Acid
• 3-Hydroxyacyl CoA Dehydrogenases
• EHHADH protein, human
• Ehhadh protein, mouse
• Enoyl-CoA Hydratase
• Peroxisomal Bifunctional Enzyme
• Isomerases
• ciprofibrate

Topics

• 3-Hydroxyacyl CoA Dehydrogenases (biosynthesis)
• Animals
• Base Sequence
• Clofibric Acid (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Enoyl-CoA Hydratase (biosynthesis)
• Fibric Acids
• Gene Expression Regulation, Enzymologic
• Humans
• Isomerases (biosynthesis)
• Mice
• Mice, Transgenic
• Microbodies (drug effects, enzymology, metabolism)
• Molecular Sequence Data
• Multienzyme Complexes (biosynthesis)
• Mutation
• Oxidation-Reduction
• Peroxisomal Bifunctional Enzyme
• Protein Binding
• Protein Conformation
• Rats
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Receptors, Retinoic Acid (genetics, metabolism)
• Receptors, Thyroid Hormone (metabolism)
• Recombinant Fusion Proteins (biosynthesis)
• Retinoid X Receptors
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Triiodothyronine (pharmacology)