Background: Examining the TR␤1 cistrome in mouse liver is critical to understanding thyroid hormone signaling. Results: Novel mechanisms of positive versus negative regulation by biotinylated TR␤1 were identified. Conclusion: TR␤1 regulates transcription by changes in relative binding and use of preferred binding motifs. Significance: This study demonstrates that a mechanism other than differential co-regulator recruitment is involved in transcriptional regulation by TR␤1

In humans, there is a significant decrease in serum T(3) and increase in rT(3) at different time points after myocardial infarction, whereas serum TSH and T(4) remain unaltered. We report here a time course study of pituitary-thyroid function and thyroid hormone metabolism in rats subjected to myocardial infarction by left coronary ligation (INF). INF- and sham-operated animals were followed by serial deiodination assays and thyroid function tests, just before, and 1, 4, 8, and 12 wk after surgery. At 4 and 12 wk after INF, liver type 1 deiodinase activity was significantly lower, confirming tissue hypothyroidism. Type 3 deiodinase (D3) activity was robustly induced 1 wk after INF only in the infarcted myocardium. Reminiscent of the consumptive hypothyroidism observed in patients with large D3-expressing tumors, this induction of cardiac D3 activity was associated with a decrease in both serum T(4) ( approximately 50% decrease) and T(3) (37% decrease), despite compensatory stimulation of the thyroid. Thyroid stimulation was documented by both hyperthyrotropinemia and radioiodine uptake. Serum TSH increased by 4.3-fold in the first and 3.1-fold in the fourth weeks (P < 0.01), returning to the basal levels thereafter. Thyroid sodium/iodide-symporter function increased 1 wk after INF, accompanying the increased serum TSH. We conclude that the acute decrease in serum T(4) and T(3) after INF is due to increased thyroid hormone catabolism from ectopic D3 expression in the heart.

To date no published data exist regarding the effects of chronic high-dose anabolic-androgenic steroid administration on tonic cardiac autonomic control. The aim of this study was to evaluate, by power spectral analysis of heart rate variability (HRV), the effects of chronic treatment with supraphysiological doses of nandrolone decanoate (DECA) on tonic cardiac autonomic regulation in sedentary rats. Male Wistar rats were treated weekly with 10 mg kg(-1) of DECA (n=7) or vehicle (CONTROL, n=7) for 10 weeks. At the 8th week of treatment, electrocardiogram was recorded in the conscious state, for time- and frequency-domain HRV analysis. Parasympathetic indexes were reduced in DECA group: high-frequency power (CONTROL=11.1+/-3.0 ms2 vs. DECA=3.8+/-0.6 ms2, P<0.05), RMSSD (CONTROL=5.9+/-0.9 ms vs. DECA 3.5+/-0.3 ms; P<0.05) and pNN5 (CONTROL=31.5+/-7.5 ms vs. DECA=13.2+/-2.6 ms; P<0.05). The sympathetic index LF/HF tended to be higher in DECA group (CONTROL=0.65+/-0.15 vs. DECA=1.17+/-0.26, P=0.0546). In conclusion, chronic treatment with DECA, in rats, impairs tonic cardiac autonomic regulation, which may provide a key mechanism for anabolic steroid-induced arrhythmia and sudden cardiac death.

Thyroid hormone (TH) signaling plays an important role in development and adult life. Many organisms may have evolved under selective pressure of exogenous TH, suggesting that thyroid hormone signaling is phylogenetically older than the systems that regulate their synthesis. Therefore, the negative feedback system by TH itself was probably the first mechanism of regulation of circulating TH levels. In humans and other vertebrates, it is well known that TH negatively regulates its own production through central actions that modulate the hypothalamic-pituitary-thyroid (HPT) axis. Indeed, primary hypothyroidism leads to the up-regulation of the genes encoding many key players in the HPT axis, such as TRH, type 2 deiodinase (dio2), pyroglutamyl peptidase II (PPII), TRH receptor 1 (TRHR1), and the TSH α- and β-subunits. However, in many physiological circumstances, the activity of the HPT axis is not always a function of circulating TH concentrations. Indeed, circadian changes in the HPT axis activity are not a consequence of oscillation in circulating TH levels. Similarly, during reduced food availability, several components of the HPT axis are down-regulated even in the presence of lower circulating TH levels, suggesting the presence of a regulatory pathway hierarchically higher than the feedback system. This minireview discusses the neural regulation of the HPT axis, focusing on both TH-dependent and -independent pathways and their potential integration.

TSH is the most important biomarker in the interpretation of thyroid function in man. Its levels are determined by circulating thyroid hormone (TH) levels that feed back centrally to regulate the expression of the subunits that comprise TSH from the pituitary. The nuclear corepressor 1 (NCoR1), is a critical coregulator of the TH receptor (TR) isoforms. It has been established to play a major role in the control of TSH secretion, because mice that express a mutant NCoR1 allele (NCoRΔID) that cannot interact with the TR have normal TSH levels despite low circulating TH levels. To determine how NCoR1 controls TSH secretion, we first developed a mouse model that allowed for induction of NCoRΔID expression postnatally to rule out a developmental effect of NCoR1. Expression of NCoRΔID postnatally led to a drop in TH levels without a compensatory rise in TSH production, indicating that NCoR1 acutely controls both TH production and feedback regulation of TSH. To demonstrate that this was a cell autonomous function of NCoR1, we expressed NCoRΔID in the pituitary using a Cre driven by the glycoprotein α-subunit promoter (P-ΔID mice). Importantly, P-ΔID mice have low TH levels with decreased TSH production. Additionally, the rise in TSH during hypothyroidism is blunted in P-ΔID mice. Thus, NCoR1 plays a critical role in TH-mediated regulation of TSH in the pituitary by regulating the repressive function of the TR. Furthermore, these studies suggest that endogenous NCoR1 levels in the pituitary could establish the set point of TSH secretion.

Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TR␤) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1 ؊/؊ mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TR␤, termed NCoR⌬ID, have low TH levels and normal TSH. We hypothesized that Src-1 T he maintenance of thyroid hormone (TH) levels is essential for development, metabolism, energy expenditure, and thermoregulation. TH levels are sustained by a negative-feedback loop within the hypothalamic-pituitary-thyroid (HPT) axis that operates to keep TH levels, both the predominant form, thyroxine (T 4 ), and the active form, triiodothryonine (T 3 ), within a precise range (1). Thyrotropin-releasing hormone (TRH) from the paraventricular nucleus of the hypothalamus (PVH) stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary. TSH acts on the thyroid to synthesize and release TH, which then signals back to both the PVH and pituitary to suppress TRH and TSH levels, respectively (2). At the molecular level, T 3 mediates its actions through its nuclear receptor isoforms, thyroid hormone receptor alpha (TR␣) and TR␤ (encoded by Thra and Thrb), which function as ligand-dependent transcription factors to either increase or decrease expression of target genes (3-5). Classically, on positively regulated TH targets, the presence of T 3 allows the binding of coactivators, such as the steroid receptor coactivator family (SRC-1, -2, and -3) (6-8). These coactivators then recruit machinery to allow the activation of gene expression (9-12). In the absence of ligand, corepressors, such as nuclear corepressor 1 (NCoR1) or silencing mediator of retinoic acid (SMRT, or NCoR2), bind and recruit complexes to repress transcription (13-18). The processes by which negative TH targets are repressed or transcribed are not well understood, but active T 3 repression does require .In previous reports, our laboratory has demonstrated that NCoR1 also mediates T 3 sensitivity and is critical in maintaining normal TH levels (23-25). NCoR1 binds to TR through two of its three nuclear-receptor-interacting domains, N2 and N3 (26-32). Mice globally expressing a conditional Ncor1 allele lacking N2 and N3, termed NCoR⌬ID, either during embryogenesis or postnatally, have decreased levels of T 4 and T 3 and normal TSH levels (24,25). In addition to altering the set point of the HPT axis, NCoR⌬ID increases the sensitivity of peripheral tissues, such as the liver, to T 3 . This enhanced sensitivity leads to the increased activation of target genes in the presence of similar amounts of T 3 (24). The role of NCoR1 in determining ligand sensitivity in the context of nuclear receptor signaling has been demonstrated by other groups using a mouse model with disrupted interaction between NCoR1 and histone deacetylase 3 (H...

These data clearly shows that G-CSF treatment was unable to prevent cardiac remodeling or to improve cardiovascular function in a rat model of acute myocardial infarction, by permanent LAD ligation, despite bone marrow stem cell mobilization.

Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner. NCoRΔID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TRβ1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance. IntroductionCholesterol metabolism in the liver is critical for normal systemic regulation of serum cholesterol levels and eventual cardiac risk. Both the thyroid hormone receptor (TR) and liver X receptor (LXR) regulate multiple cholesterol clearance pathways and have been targeted as potential therapeutic avenues to improve cholesterol metabolism in humans (1-4). Thyroid hormone (TH) and its liver-specific analogs have been shown to lower serum cholesterol levels through increased expression of the LDL-R and/or HDL receptor SR-B1 in the liver (2, 5, 6), stimulate cholesterol elimination via conversion to bile acids (3, 5, 7-9), enhance biliary cholesterol excretion through ATP-binding cassette transporter G5 and G8 (ABCG5/G8), and decrease cholesterol absorption (10-12). The effects of TH on the cholesterol metabolism in the liver are mediated by the TRβ1 isoform (7, 13).LXRα and LXRβ are activated by oxysterols and act as intracellular cholesterol sensors (14). LXRα is the major isoform in the liver that plays a predominant role in maintaining hepatic cholesterol homeostasis. Global or liver-specific KO of Lxra leads to a dramatic hepatic cholesterol accumulation in mice fed diets with high cholesterol content (15-17). LXRα controls cholesterol clearance through regulation of intestinal cholesterol absorption and biliary cholesterol secretion as well as cholesterol conversion into bile acids (15,(17)(18)(19). Thus, TRβ1 and LXRα regulate both distinct and overlapping pathways to control cholesterol metabolism in the liver. Based on this, we hypothesized that targeting common nuclear receptor (NR) coregulators could amplify beneficial effects of both pathways on cholesterol metabolism.Previous work from our laboratory and others has demonstrated that the NR corepressor, nuclear corepressor 1 (N...