The dominant negative thyroid hormone receptor β mutant Δ337T alters PPARα signaling in heart

PPAR alpha and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPAR alpha regulation of target genes and used mice exhibiting a cardioselective Delta 337T TR beta 1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TR alpha and TR beta. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic ( MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPAR alpha ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPAR alpha, TR alpha 2, RXR beta, or PGC-1 alpha. However, protein content for TR alpha 1 and the PPAR alpha heterodimeric partner RXR alpha was diminished in MUT, whereas PPAR beta increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The nonligand-binding TR beta 1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPAR alpha ligands may be determined by thyroid hormone state and TR function.