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.
Subject(s)
Fatty Acids/metabolism , Mutant Proteins/physiology , PPAR alpha/antagonists & inhibitors , Thyroid Hormone Receptors alpha/physiology , Animals , Fatty Liver/genetics , Glycogen/metabolism , Lipid Metabolism/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxidation-Reduction , Regulatory Elements, Transcriptional , Signal Transduction , Thyroid Hormone Receptors alpha/genetics , Transcriptional ActivationABSTRACT
OBJECTIVE: To describe a patient who presented with anaplastic thyroid carcinoma and thyrotoxicosis in whom hypoparathyroidism developed. METHODS: We present the clinical and laboratory findings in a patient with anaplastic thyroid carcinoma and thyrotoxicosis. We also review the literature for previous cases of anaplastic thyroid carcinoma with thyrotoxicosis. RESULTS: A 74-year-old man presented with left-sided neck pain and a rapidly enlarging neck mass. Initial thyroid function tests revealed the following: thyrotropin (thyroid-stimulating hormone or TSH) 0.03 microIU/mL, free thyroxine 1.28 ng/dL, and total triiodothyronine 119 ng/dL. A thyroid radioiodine uptake scan was 2.2% at 25 hours. Pathology examination of the neck mass disclosed anaplastic thyroid carcinoma. His thyrotoxicosis was managed with beta-adrenergic blockade. The thyroid carcinoma was treated palliatively with external beam irradiation. During week 9 after the patient's initial presentation, symptomatic hypocalcemia developed, with an ionized serum calcium level of 0.75 mmol/L (normal range, 1.15 to 1.29) and a parathyroid hormone level of 21.2 pg/mL (normal range, 10 to 65). He was given calcium gluconate intravenously for initial management, followed by orally administered calcium carbonate and calcitriol. At week 15, he died of complications attributable to anaplastic thyroid carcinoma. CONCLUSION: Thyrotoxicosis due to thyroiditis is a rare initial manifestation of anaplastic thyroid carcinoma. Hypoparathyroidism due to anaplastic thyroid carcinoma has not been reported previously.
