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Title: The dominant negative thyroid hormone receptor beta-mutant delta337T alters PPAR-alpha signaling in heart

Author
item BUROKER, N - UNIV WASHINGTON SOM
item Young, Martin
item WEI, C - UTMDACC
item SERIKAWA, K - UNIV WASHINGTON SOM
item GE, M - UNIV WASHINGTON SOM
item NING, X-H - UNIV WASHINGTON SOM
item PORTMAN, M - UNIV WASHINGTON SOM

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/12/2006
Publication Date: 2/20/2007
Citation: Buroker, N.E., Young, M.E., Wei, C., Serikawa, K., Ge, M., Ning, X., Portman, M.A. 2007. The dominant negative thyroid hormone receptor beta-mutant delta337T alters PPAR-alpha signaling in heart. American Journal of Physiology - Endocrinology and Metabolism. 292:E453-E460.

Interpretive Summary: Thyroid hormone acts by switching genes on or off. Fat also switches a number of genes on or off. In several disease states that affect the American population, such as diabetes and cardiovascular (e.g., heart) disease, levels of fats and thyroid hormone are altered in the blood. These alterations in blood fats and thyroid hormone have been implicated in heart disease development. Also, genes become switched on and off during heart disease. The purpose of our study was to determine if fats and thyroid hormones switch genes on and off in a similar or dissimilar way in the heart. The results show that fats and thyroid hormone affect each other's ability to switch genes on and off in the heart. This work is important for improving our understanding as to why humans with distinct endocrine diseases (e.g., hyperthyroidism, diabetes mellitus) have increased risk for heart disease development.

Technical Abstract: PPARalpha 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 PPARalpha regulation of target genes and used mice exhibiting a cardioselective Delta337T TRbeta1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TRalpha and TRbeta. 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 PPARalpha 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, PPARalpha, TRalpha2, RXRbeta, or PGC-1alpha. However, protein content for TRalpha1 and the PPARalpha heterodimeric partner RXRalpha was diminished in MUT, whereas PPARbeta 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 non-ligand-binding TRbeta1 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 PPARalpha ligands may be determined by thyroid hormone state and TR function.