Thyroid hormone interacts with PPARalpha and PGC-1 during mitochondrial maturation in sheep heart. Academic Article uri icon

Overview

abstract

  • Thyroid hormone (TH) promotes cardiac mitochondrial maturation and substrate metabolism after birth. This regulation involves ligand-dependent binding of nuclear TH receptors to target gene elements. TH also putatively controls genes indirectly by modulating transcription and/or translation of other nuclear steroid receptors and coactivators, such as peroxisome proliferator-activated receptor-alpha (PPARalpha) and peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPARalpha and PGC-1 regulation of metabolic genes during postnatal maturation in sheep heart in vivo. We measured their mRNAs and/or protein levels and downstream targets in left ventricle from lambs: fetal (F), 30-day-old after postnatal thyroidectomy (THY), and 30-day-old euthyroid (Con). Both PPARalpha and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPARalpha did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPARalpha, nuclear respiratory factor-1 and hypoxia-inducible factor-1alpha. THY promotion in PPARalpha mRNA did not change PPARalpha protein or mRNA for PPARalpha target genes, pyruvate-dehydrogenase kinase 4 (PDK4) and muscle type carnitine palmitoyltransferase I (mCPTI). THY reduction in PGC-1 protein occurred, while reducing cytochrome c oxidase and cytochrome c content and decreasing cardiac maximal inherent respiratory capacity. These data imply that TH modulates mitochondrial maturation partly through posttranscriptional control of PGC-1, while any important regulation of PDK4 and mCPTI by change in PPARalpha protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.

publication date

  • July 15, 2005

Research

keywords

  • Heart
  • Mitochondria, Heart
  • PPAR alpha
  • Thyroid Hormones
  • Transcription Factors

Identity

Scopus Document Identifier

  • 27144444345

Digital Object Identifier (DOI)

  • 10.1152/ajpheart.00473.2005

PubMed ID

  • 16024569

Additional Document Info

volume

  • 289

issue

  • 5