P-62 Regulation of suppressor of cytokine signalling-2 gene expression in liver and kidney by estradiol, growth hormone and thyroid hormone interaction

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

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Ligand-dependent, Pit-1/growth hormone factor-1 (GHF-1)-independent transcriptional stimulation of rat growth hormone gene expression by thyroid hormone receptors in vitro

Molecular and Cellular Biology ◽

10.1128/mcb.13.3.1719-1727.1993 ◽

1993 ◽

Vol 13 (3) ◽

pp. 1719-1727

Author(s):

C S Suen ◽

W W Chin

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Thyroid Hormone ◽

Promoter Activity ◽

Hormone Receptors ◽

Nuclear Extract ◽

In Vitro Transcription ◽

Stimulation Of ◽

Transcriptional Stimulation

The expression of the rat growth hormone (rGH) gene in the anterior pituitary gland is modulated by Pit-1/GHF-1, a pituitary-specific transcription factor, and by other more widely distributed factors, such as the thyroid hormone receptors (TRs), Sp1, and the glucocorticoid receptor. Thyroid hormone (T3)-mediated transcriptional stimulation of rGH gene expression has been extensively studied in vivo and in vitro including the measurements of (i) rGH mRNA by blot hybridization, (ii) transcriptional rate of rGH gene by nuclear run-on, and (iii) reporter gene expression in which a chimeric plasmid containing 5'-flanking sequences of the rGH gene linked to a reporter gene has been transfected either stably or transiently into pituitary and/or nonpituitary cells. From these studies, it has been suggested that the Pit-1/GHF-1 binding site is necessary for full T3 action. We developed a cell-free in vitro transcription system to examine further the roles of the TRs and Pit-1/GHF-1 in rGH gene activation. Using GH3 nuclear extract as a source of TRs and Pit-1/GHF-1, this in vitro transcription assay showed that T3 stimulation of rGH promoter activity is dependent on the addition of T3 to the GH3 nuclear extract. This transcriptional stimulation was augmented with increasing concentrations of ligand and was T3, but not T4 or reverse T3, specific. T3-mediated stimulation of rGH promoter activity was completely abolished by preincubation of the nuclear extract with rGH-thyroid hormone response element (-200 to -160) but not with Pit-1/GHF-1 (-137 to -65) oligonucleotides. Further, neither deletion of both Pit-1/GHF-1 binding sites nor mutation of the proximal Pit-1/GHF-1 binding site from the rGH promoter abrogated the T3 effect. These results provide evidence that T3-stimulated rGH promoter activity is independent of Pit-1/GHF-1 and raise the possibility that the stimulation of rGH gene expression by T3 might involve direct interaction of TRs with the general transcriptional apparatus.

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Vitamin D interferes with transactivation of the growth hormone gene by thyroid hormone and retinoic acid.

Molecular and Cellular Biology ◽

10.1128/mcb.16.1.318 ◽

1996 ◽

Vol 16 (1) ◽

pp. 318-327 ◽

Cited By ~ 45

Author(s):

P Garcia-Villalba ◽

A M Jimenez-Lara ◽

A Aranda

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Vitamin D ◽

Retinoic Acid ◽

Thyroid Hormone ◽

Vitamin D Receptor ◽

Growth Hormone Gene ◽

Dependent Manner ◽

Transcriptional Responses ◽

Response Element

The thyroid hormone, retinoic acid (RA), and vitamin D regulate gene expression by binding to similar receptors which act as ligand-inducible transcription factors. Incubation of pituitary GH4C1 cells with nanomolar concentrations of vitamin D markedly reduces the response of the rat growth hormone mRNA to thyroid hormone triiodothyronine (T3) and RA. The stimulation of growth hormone gene expression by both ligands is mediated by a common hormone response element (TREGH) present in the 5'-flanking region of the gene, and the inhibition caused by vitamin D is due to transcriptional interference of the vitamin D receptor on this DNA element. No inhibition of the basal promoter activity by the vitamin was observed. The response to T3 and RA of a heterologous promoter containing this element, the palindromic T3- and RA-responsive sequence TREPAL, or a direct repeat of the same motif is also inhibited by vitamin D. In contrast, vitamin D strongly induces the activity of constructs containing a vitamin D response element, and neither T3 nor RA reduces vitamin D-mediated transactivation. Transfection with an expression vector for the retinoid X receptor alpha (RXR alpha) increases transactivation by T3 and RA but does not abolish the inhibition caused by the vitamin. Gel retardation experiments show that the vitamin D receptor (VDR) as a heterodimer with RXR weakly binds to the T3- and RA-responsive elements. Additionally, VDR displaces binding of T3 and RA receptors in a dose-dependent manner. Our data suggest the formation of TR-VDR and RAR-VDR heterodimers with RXR. The fact that the same response element mediates opposite effects of at least four different nuclear receptors provides a greater complexity and flexibility of the transcriptional responses to their ligands.

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Stimulatory effect of thyroid hormone on growth hormone gene expression in a human pituitary cell line.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.77.1.8325953 ◽

1993 ◽

Vol 77 (1) ◽

pp. 281-285

Author(s):

P Chomczynski ◽

P A Soszynski ◽

L A Frohman

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Thyroid Hormone ◽

Cell Line ◽

Pituitary Cell ◽

Growth Hormone Gene ◽

Human Pituitary

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Septic shock non-thyroidal illness syndrome causes hypothyroidism and conditions for reduced sensitivity to thyroid hormone

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0188 ◽

2013 ◽

Vol 50 (2) ◽

pp. 255-266 ◽

Cited By ~ 19

Author(s):

Isabel Castro ◽

Leah Quisenberry ◽

Rosa-Maria Calvo ◽

Maria-Jesus Obregon ◽

Joaquin Lado-Abeal

Keyword(s):

Gene Expression ◽

Septic Shock ◽

Thyroid Hormone ◽

Tissue Level ◽

Binding Activity ◽

Monocarboxylate Transporter ◽

Kidney Cortex ◽

Liver And Kidney ◽

Response To Stress

Non-thyroidal illness syndrome (NTIS) is part of the neuroendocrine response to stress, but the significance of this syndrome remains uncertain. The aim of this study was to investigate the effect of lipopolysaccharide (LPS)-induced NTIS on thyroid hormone (TH) levels and TH molecular targets, as well as the relationship between septic shock nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and TH receptor β (THRB) gene expression at a multi-tissue level in a pig model. Prepubertal domestic pigs were given i.v. saline or LPS for 48 h. Serum and tissue TH was measured by chemiluminescence and RIA. Expression of THRs and cofactors was measured by real-time PCR, and deiodinase (DIO) activity was measured by enzyme assays. Tissue NF-kB nuclear binding activity was evaluated by EMSA. LPS-treated pigs had decreased TH levels in serum and most tissues. DIO1 expression in liver and kidney and DIO1 activity in kidney decreased after LPS. No changes in DIO2 activity were observed between groups. LPS induced an increase in hypothalamus, thyroid, and liver DIO3 activity. Among the other studied genes, monocarboxylate transporter 8 and THRB were the most commonly repressed in endotoxemic pigs. LPS-induced NF-kB activation was associated with a decrease in THRB gene expression only in frontal lobe, adrenal gland, and kidney cortex. We conclude that LPS-induced NTIS in pigs is characterized by hypothyroidism and tissue-specific reduced TH sensitivity. The role of NF-kB in regulating THRB expression during endotoxemia, if any, is restricted to a limited number of tissues.

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