A Mutant Thyroid Hormone Receptor α Antagonizes Peroxisome Proliferator-Activated Receptor α Signalingin Vivoand Impairs Fatty Acid Oxidation

Abstract

Thyroid hormone regulates the balance between lipolysis and lipogenesis. We previously reported that male mice with a dominant-negative P398H mutation introduced into the TRalpha gene have visceral obesity, hyperleptinemia, and reduced catecholamine-stimulated lipolysis in white adipose tissue. Based on our observation of hepatic steatosis in the TRalpha P398H male mice, we used in vitro and in vivo models to investigate the influence of the TRalpha P398H mutant on peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling. Wild-type TRalpha and the P398H mutant significantly reduced PPARalpha-mediated transcription in transient transfection assays. T(3) reversed the inhibition of PPARalpha action by wild-type TRalpha but not the P398H mutant. Chromatin immunoprecipitation assays demonstrated that the P398H mutant reduces PPARalpha binding to peroxisome proliferator receptor elements. In gel shift assays, the P398H mutant directly bound the peroxisome proliferator-activated receptor response element and inhibited PPARalpha binding, which was not reversed by addition of retinoid X receptor. The TRalpha R384C and PV dominant-negative mutants are not associated in vivo with a metabolic phenotype and had reduced (PV) or absent (R384C) PPARalpha inhibition compared with P398H. The metabolic phenotype of the P398H mutant mice is due, in part, to unique properties of the P398H mutant receptor interfering with PPARalpha signaling. The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPARalpha interactions.

Role of Pyruvate Dehydrogenase Inhibition in the Development of Hypertrophy in the Hyperthyroid Rat Heart

“…[33][34][35] The increase in circulating fatty acids is likely to be secondary to an increase in lipolysis in the white adipose tissue, which is known to be regulated in part by thyroid hormone. 36 We also found evidence of upregulation of several important energy-generating metabolic pathways. The ex vivo metabolomic experiments provided evidence of increased cardiac glucose use in rats treated with T3, despite the reduction in PDH flux.…”

Thyroid hormone contributes to the hypolipidemic effect of polyunsaturated fatty acids from fish oil: in vivo evidence for cross talking mechanisms

“…Not only do they coregulate specific genes but the activity or availability of one receptor can influence the other's activity (Lu & Cheng 2010). It has been demonstrated, both in transgenic animals and in cell transfection assays, that TR, in the absence of T 3 binding, is able to reduce PPARa-mediated transcription (Buroker et al 2007, Liu et al 2007, Ying et al 2007). This mechanism is particularly of interest to hypothyroid status, since the unliganded TR may blunt not only the action of PPARa (Liu et al 2007) but also the action of other nuclear receptors in the liver, as described by others (Hashimoto et al 2006).…”

“…Currently, it is clear that the effects of nuclear receptors are not a consequence of the binding of their specific ligands alone, but also reflect interactions with other signaling pathways (Hashimoto et al 2006, Liu et al 2007. Knowing the consequences of these interactions for the in vivo effects of nuclear receptors, agonists have important implications, both at physiological and pharmacological levels.…”

Mechanisms of thyroid hormone action

“…5). In metabolic regulation, this includes potentiation of adrenergic signaling (26)(27)(28)(29) as well as direct interaction with metabolic-sensing nuclear receptors (30)(31)(32). Similar direct receptor-to-receptor interactions and competition for overlapping DNA response elements are seen in neural differentiation, as TR interacts with chicken ovalbumin upstream transcription factor 1 (COUP-TF1) and retinoic acid receptor (RAR) (3,33).…”