The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver

Thyroid hormones are galactopoietic and help to establish the mammary gland’s metabolic priority during lactation. Expression patterns for genes that can alter tissue sensitivity to thyroid hormones and thyroid hormone activity were evaluated in the mammary gland and liver of cows at 53, 35, 20, and 7 days before expected parturition, and 14 and 90 days into the subsequent lactation. Transcript abundance for the three isoforms of iodothyronine deiodinase, type I ( DIO1), type II ( DIO2) and type III ( DIO3), thyroid hormone receptors alpha1 ( TRα 1), alpha2 ( TRα 2) and beta1 ( TRβ 1), and retinoic acid receptors alpha ( RXRα) and gamma ( RXRγ), which act as coregulators of thyroid hormone receptor action, were evaluated by quantitative RT-PCR. The DIO3 is a 5-deiodinase that produces inactive iodothyronine metabolites, whereas DIO1 and DIO2 generate the active thyroid hormone, triiodothyronine, from the relatively inactive precursor, thyroxine. Low copy numbers of DIO3 transcripts were present in mammary gland and liver. DIO2 was the predominant isoform expressed in mammary gland and DIO1 was the predominant isoform expressed in liver. Quantity of DIO1 mRNA in liver tissues did not differ with physiological state, but tended to be lowest during lactation. Quantity of DIO2 mRNA in mammary gland increased during lactation ( P < 0.05), with copy numbers at 90 days of lactation 6-fold greater than at 35 and 20 days prepartum. When ratios of DIO2/DIO3 mRNA were evaluated, the increase was more pronounced (>100-fold). Quantity of TRβ 1 mRNA in mammary gland increased with onset of lactation, whereas TRα 1 and TRα 2 transcripts did not vary with physiological state. Conversely, quantity of RXRα mRNA decreased during late gestation to low levels during early lactation. Data suggest that increased expression of mammary TRβ 1 and DIO2, and decreased RXRα, provide a mechanism to increase thyroid hormone activity within the mammary gland during lactation.

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Bromine and thyroid hormone activity.

Journal of Clinical Pathology ◽

10.1136/jcp.46.5.456 ◽

1993 ◽

Vol 46 (5) ◽

pp. 456-458 ◽

Cited By ~ 4

Author(s):

P Allain ◽

S Berre ◽

N Krari ◽

P Laine ◽

N Barbot ◽

...

Keyword(s):

Thyroid Hormone ◽

Hormone Activity

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Heterogeneity and neurovascular integration of intraportally transplanted islets revealed by 3-D mouse liver histology

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00605.2020 ◽

2021 ◽

Author(s):

Chien-Chia Chen ◽

Shih-Jung Peng ◽

Pei-Yu Wu ◽

Hung-Jen Chien ◽

Chih-Yuan Lee ◽

...

Keyword(s):

Islet Transplantation ◽

Mouse Liver ◽

Image Data ◽

Liver Histology ◽

Systematic Assessment ◽

3 Dimensional ◽

Neural Integration ◽

Quantitative Analyses ◽

Graft Tissue

Background: Intraportal islet transplantation has been clinically applied for treatment of unstable type 1 diabetes. However, in the liver, systematic assessment of the dispersed islet grafts and the graft-hepatic integration remains difficult, even in animal models. This is due to the lack of global and in-depth analyses of the transplanted islets and their microenvironment. Here, we apply 3-dimensional (3-D) mouse liver histology to investigate the islet graft microstructure, vasculature, and innervation. Methods: Streptozotocin-induced diabetic mice were used in syngeneic intraportal islet transplantation to achieve euglycemia. Optically cleared livers were prepared to enable 3-D morphological and quantitative analyses of the engrafted islets. Results: 3-D image data reveal the clot- and plaque-like islet grafts in the liver: the former are derived from islet emboli and associated with ischemia, whereas the latter (minority) resemble the plaques on the walls of portal vessels (e.g., at the bifurcation) with mild, if any, peri-graft tissue damage. Three weeks after transplantation, both types of grafts are revascularized, yet significantly more lymphatics are associated with the plaque- than clot-like grafts. Regarding the islet reinnervation, both types of grafts connect to the peri-portal nerve plexus and develop peri- and intra-graft innervation. Specifically, the sympathetic axons and varicosities contact the α-cells, highlighting the graft-host neural integration. Conclusion/interpretation: We present the heterogeneity of the intraportally transplanted islets and the graft-host neurovascular integration in mice. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue and cellular analyses of human islet grafts in the liver.

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The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements

Molecular and Cellular Biology ◽

10.1128/mcb.13.8.5057-5069.1993 ◽

1993 ◽

Vol 13 (8) ◽

pp. 5057-5069

Author(s):

V Desai-Yajnik ◽

H H Samuels

Keyword(s):

Human Immunodeficiency Virus ◽

Thyroid Hormone ◽

Long Terminal Repeat ◽

Human Immunodeficiency Virus Type ◽

Binding Sites ◽

Nf Kappa B ◽

Response Elements ◽

Immunodeficiency Virus ◽

Hiv 1

We report that thyroid hormone (T3) receptor (T3R) can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). Purified chick T3R-alpha 1 (cT3R-alpha 1) binds as monomers and homodimers to a region in the LTR (nucleotides -104 to -75 [-104/-75]) which contains two tandem NF-kappa B binding sites and to a region (-80/-45) which contains three Sp1 binding sites. In contrast, human retinoic acid receptor alpha (RAR-alpha) and mouse retinoid X receptor beta (RXR-beta) do not bind to these elements. However, RXR-beta binds to these elements as heterodimers with cT3R-alpha 1 and to a lesser extent with RAR-alpha. Gel mobility shift assays also revealed that purified NF-kappa B p50/65 or p50/50 can bind to one but not both NF-kappa B sites simultaneously. Although the binding sites for p50/65, p50/50, and T3R, or Sp1 and T3R, overlap, their binding is mutually exclusive, and with the inclusion of RXR-beta, the major complex is the RXR-beta-cT3R-alpha 1 heterodimer. The NF-kappa B region of the LTR and the NF-kappa B elements from the kappa light chain enhancer both function as T3 response elements (TREs) when linked to a heterologous promoter. The TREs in the HIV-1 NF-kappa B sites appear to be organized as a direct repeat with an 8- or 10-bp gap between the half-sites. Mutations within the NF-kappa B motifs which eliminate binding of cT3R-alpha 1 also abolish stimulation by T3, indicating that cT3R-alpha 1 binding to the Sp1 region does not independently mediate activation by T3. The Sp1 region, however, is converted to a functionally strong TRE by the viral tat factor. These studies indicate that the HIV-1 LTR contains both tat-dependent and tat-independent TREs and reveal the potential for T3R to modulate other genes containing NF-kappa B- and Sp1-like elements. Furthermore, they indicate the importance of other transcription factors in determining whether certain T3R DNA binding sequences can function as an active TRE.

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Increased invasive activity of human hepatocellular carcinoma cells is associated with an overexpression of thyroid hormone Î²1 nuclear receptor and low expression of the anti-metastatic nm23 gene

Cancer Letters ◽

10.1016/0304-3835(95)04000-t ◽

1995 ◽

Vol 98 (1-2) ◽

pp. 89-95 ◽

Cited By ~ 1

Author(s):

L Kwang-huei

Keyword(s):

Hepatocellular Carcinoma ◽

Thyroid Hormone ◽

Nuclear Receptor ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Hepatocellular Carcinoma Cells ◽

Nm23 Gene ◽

Human Hepatocellular Carcinoma Cells ◽

Low Expression

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The Immune System as a Regulator of Thyroid Hormone Activity

Experimental Biology and Medicine ◽

10.1177/153537020623100301 ◽

2006 ◽

Vol 231 (3) ◽

pp. 229-236 ◽

Cited By ~ 46

Author(s):

John R. Klein

Keyword(s):

Bone Marrow ◽

Immune System ◽

Thyroid Hormone ◽

Bone Marrow Cells ◽

Acute Infection ◽

Hormone Secretion ◽

Thyroid Stimulating Hormone ◽

Pituitary Cells ◽

Hormone Activity ◽

Endocrine Activity

It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells-including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes—the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to micro-regulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyrold connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection.

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Ontogenetic profile and thyroid hormone regulation of type-1 and type-8 glucose transporters in rat Sertoli cells

International Journal of Andrology ◽

10.1111/j.1365-2605.2005.00516.x ◽

2005 ◽

Vol 28 (2) ◽

pp. 99-106 ◽

Cited By ~ 32

Author(s):

ELEONORA CAROSA ◽

CARLA RADICO ◽

NADIA GIANSANTE ◽

SIMONA ROSSI ◽

FABIO D'ADAMO ◽

...

Keyword(s):

Thyroid Hormone ◽

Sertoli Cells ◽

Glucose Transporters ◽

Hormone Regulation

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Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Cancers ◽

10.3390/cancers13194972 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4972

Author(s):

Sanjeev Kumar ◽

Allegra Freelander ◽

Elgene Lim

Keyword(s):

Breast Cancer ◽

Nuclear Receptors ◽

Nuclear Receptor ◽

Patient Outcomes ◽

Estrogen Receptor Α ◽

Receptor Activity ◽

Breast Cancers ◽

Cancer Subtypes ◽

Major Breast

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

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