Thyroid hormone receptor beta (THRβ1) is the major regulator of T3 action in human iPSC-derived hepatocytes.

Objective: Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood.

Methods: To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC).

Nuclear Receptor Corepressors NCOR1 and SMRT Regulate Metabolism via Intestinal Regulation of Carbohydrate Transport.

Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity, and energy expenditure, representing an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable.

The Differential Effect of a Shortage of Thyroid Hormone Compared with Knockout of Thyroid Hormone Transporters Mct8 and Mct10 on Murine Macrophage Polarization.

Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters.

Intestinal permeability is associated with aggravated inflammation and myofibroblast accumulation in Graves' orbitopathy: the MicroGO study.

Background: Graves' disease (GD) and Graves' orbitopathy (GO) result from ongoing stimulation of the TSH receptor due to autoantibodies acting as persistent agonists. Orbital pre-adipocytes and fibroblasts also express the TSH receptor, resulting in expanded retro-orbital tissue and causing exophthalmos and limited eye movement. Recent studies have shown that GD/GO patients have a disturbed gut microbiome composition, which has been associated with increased intestinal permeability.

Comparative Analysis of Taxonomic and Functional Gut Microbiota Profiles in Relation to Seroconversion of Thyroid Peroxidase Antibodies in Euthyroid Participants.

Previous studies have reported gut microbiome alterations in Hashimoto's autoimmune thyroiditis (HT) patients. Yet, it is unknown whether an aberrant microbiome is present before clinical disease onset in participants susceptible to HT or whether it reflects the effects of the disease itself. In this study, we report for the first time a comprehensive characterization of the taxonomic and functional profiles of the gut microbiota in euthyroid seropositive and seronegative participants.

Protocol for a double-blinded randomised controlled trial to assess the effect of faecal microbiota transplantations on thyroid reserve in patients with subclinical autoimmune hypothyroidism in the Netherlands: the IMITHOT trial.

Background: Hashimoto's thyroiditis (HT) is a common endocrine autoimmune disease affecting roughly 5% of the general population and involves life-long treatment with levothyroxine, as no curative treatment yet exists. Over the past decade, the crosstalk between gut microbiota and the host immune system has been well-recognised, identifying the gut microbiome as an important factor in host health and disease, including susceptibility to autoimmune diseases. Previous observational studies yielded a link between disruption of the gut microbiome composition and HT.

A Comprehensive Review of Thyroid Hormone Metabolism in the Gut and Its Clinical Implications.

The gut is a target organ of thyroid hormone (TH) that exerts its action via the nuclear thyroid hormone receptor α1 (TRα1) expressed in intestinal epithelial cells. THs are partially metabolized via hepatic sulfation and glucuronidation, resulting in the production of conjugated iodothyronines. Gut microbiota play an important role in peripheral TH metabolism as they produce and secrete enzymes with deconjugation activity (β-glucuronidase and sulfatase), via which TH can re-enter the enterohepatic circulation.

Levothyroxine use and the risk of colorectal cancer: a large population-based case-control study.

Objective: Whether an association between oral levothyroxine use, leading to supraphysiological exposure of the colon to thyroid hormones, and risk of colorectal cancer exists in humans is unclear. We therefore aimed to assess whether the use of levothyroxine is associated with a reduced risk of colorectal cancer in a linked cohort of pharmacy and cancer data.

Design: Population-based matched case-control study.

Thyroid Hormone and Deiodination in Innate Immune Cells.

Thyroid hormone has recently been recognized as an important determinant of innate immune cell function. Highly specialized cells of the innate immune system, including neutrophils, monocytes/macrophages, and dendritic cells, are capable of identifying pathogens and initiating an inflammatory response. They can either phagocytose and kill microbes, or recruit other innate or adaptive immune cells to the site of inflammation.

Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function.

Innate immune cells, including macrophages, have recently been identified as target cells for thyroid hormone. We hypothesized that optimal intracellular concentrations of the active thyroid hormone triiodothyronine (T3) are essential for proinflammatory macrophage function. T3 is generated intracellularly by type 2 deiodinase (D2) and acts via the nuclear thyroid hormone receptor (TR).

The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Optimal Neutrophil Function: Observations From Three Species.

Neutrophils are essential effector cells of the innate immune system that have recently been recognized as thyroid hormone (TH) target cells. Cellular TH bioavailability is regulated by the deiodinase enzymes, which can activate or inactivate TH. We have previously shown that the TH inactivating enzyme type 3 deiodinase (D3) is present in neutrophils.

Increased circulating interleukin-8 in patients with resistance to thyroid hormone receptor α.

Innate immune cells have recently been identified as novel thyroid hormone (TH) target cells in which intracellular TH levels appear to play an important functional role. The possible involvement of TH receptor alpha (TRα), which is the predominant TR in these cells, has not been studied to date. Studies in TRα mice suggest a role for this receptor in innate immune function.

Transfusion of 35-day-stored red blood cells does not alter lipopolysaccharide tolerance during human endotoxemia.

Background: Transfusion-related immunomodulation (TRIM) encompasses immunosuppressive and proinflammatory effects induced by red blood cell (RBC) transfusion. Changes that occur during storage in the RBC product have been hypothesized to underlie TRIM, mediated by tolerance of toll-like receptors (TLR). We investigated whether transfusion of 35-day-stored autologous RBCs alters cytokine production in response to stimulation with lipopolysaccharide (LPS) or lipotheic acid (LTA), in a clinically relevant model of endotoxemia.

Tissue thyroid hormone metabolism is differentially regulated during illness in mice.

Illness induces major modifications in central and peripheral thyroid hormone (TH) metabolism, so-called nonthyroidal illness syndrome (NTIS). As a result, organ-specific changes in local TH availability occur depending on the type and severity of illness. Local TH availability is of importance for the regulation of the tissue-specific TH target genes and determined by the interplay between deiodinating enzymes, TH transport and TH receptor (TR) expression.

The classic pathways of thyroid hormone metabolism.

Thyroid hormones (TH) are crucial for growth and development and play an important role in energy homeostasis. Although serum TH levels are relatively constant in the physiological state, TH bioavailability at the tissue and cellular level is dependent on local TH metabolism. Circulating TH produced by the thyroid can be metabolized by a number of different pathways resulting in 1) activation of TH 2) deactivation of TH or 3) excretion of TH and subsequent metabolites.

Thyroid hormone metabolism in innate immune cells.

Thyroid hormone (TH) metabolism and thyroid status have been linked to various aspects of the immune response. There is extensive literature available on the effects of thyroid hormone on innate immune cells. However, only recently have authors begun to study the mechanisms behind these effects and the role of intracellular TH metabolism in innate immune cell function during inflammation.

The Thyroid Hormone Inactivating Enzyme Type 3 Deiodinase is Present in Bactericidal Granules and the Cytoplasm of Human Neutrophils.

Neutrophils are important effector cells of the innate immune system. Thyroid hormone (TH) is thought to play an important role in their function. Intracellular TH levels are regulated by the deiodinating enzymes.

Differential Effects of Sepsis and Chronic Inflammation on Diaphragm Muscle Fiber Type, Thyroid Hormone Metabolism, and Mitochondrial Function.

Background: The diaphragm is the main respiratory muscle, and its function is compromised during severe illness. Altered local thyroid hormone (TH) metabolism may be a determinant of impaired muscle function during illness.

Methods: This study investigates the effects of bacterial sepsis and chronic inflammation on muscle fiber type, local TH metabolism, and mitochondrial function in the diaphragm.

Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength.

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength.

Cathepsin L, target in cancer treatment?

Cathepsin L, a cysteine protease, is considered to be a potential therapeutic target in cancer treatment. Proteases are involved in the development and progression of cancer. Inhibition of activity of specific proteases may slow down cancer progression.