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Thyroid Hormone Signaling Pathway

Figure 1. Signalling pathways involved in thyroid hormone actions on hepatic lipid metabolism. The classic pathway describes the action of thyroid hormones through nuclear thyroid hormone receptors (TR), which modulate the expression of genes involved in cholesterol and lipid metabolism (bottom left). The non-classic pathway highlights the major target proteins of thyroid hormones in the cytosol: PI3K, Akt, MAPK and PKC, which contribute to the effect of T3 on SREBP1 expression, and CaMKK and AMPK, which are involved in T3-induced fatty acid (FA) oxidation. Additionally, T3-activated MAPK phosphorylates TRβ, increasing its transcriptional activityand thereby also leading to nuclear effects.

Thyroid hormone overview

The thyroid hormone signaling pathway has a wide range of functions in terms of individual development, maintenance of homeostasis, cell proliferation and differentiation, and glucose metabolism. Thyroid hormones are secreted by the thyroid gland, including thyroxine (T3) and triiodothyronine (T4). The thyroid gland is necessary for maintaining growth and development, and its insufficient or excessive secretion can cause disease. When the thyroid function is insufficient, the physical and mental development is affected, which can cause minor illnesses. When the adult thyroid dysfunction occurs, it can cause mucinous edema. Neuritis, irritability, tremors, increased heart rate, and increased cardiac output will occur during hyperthyroidism. In addition to affecting the growth and development of long bones, the thyroid hormone signaling pathway also affects the development of the brain. Insufficient thyroid hormones in infants and young children will lead to stagnation of height and mental retardation. Under normal circumstances, under the control of the central nervous system, the hypothalamic release of thyrotropin releasing hormone (TRH) regulates the secretion of pituitary thyroid stimulating hormone (TSH), which stimulates thyroid cells to secrete thyroid hormone; when the concentration of T4 and T3 in the blood increases, negative feedback inhibits the synthesis and release of pituitary TSH, reduces the response of the pituitary gland to TRH, and reduces the secretion of TSH, so that the secretion of thyroid hormone is not too high; and when the concentration of T4 and T3 in the blood decreases, the negative feedback affecting on the pituitary gland is weakened. In summary, the hypothalamic-adenohypophyseal-thyroid regulatory loop maintains a relatively constant thyroid hormone signaling pathway.

Thyroid hormone family

Thyroid hormone T3 is the main active part in the conduction of thyroid hormone signaling pathway. It exerts a wide range of physiological effects by binding to thyroid hormone receptor (TR) and participates in calories, metabolism, heart rate, renal sodium reabsorption and blood volume. Regulation TR can be divided into TRα and TRβ, where TRα is mainly distributed in the heart, brain, skeletal muscle and adipose tissue, while TRβ is mainly distributed in the liver and kidney. Human THRα and THRβ are localized on human chromosomes 17 and 3, respectively, and a variety of TR isomers can be generated by selective splicing and selection of the starting translation site. TRs consist of multiple domains. The DBD and LBD domains are highly conserved among the various isoforms of TRs, but the A/B domains of TRα and TRβ are not similar. There are many TR isomers that have been found, including TRα1, TRα2, TRα3, etc., which are produced by THRA coding, and TRβ1, TRβ2, and TRβ3, which are produced by THRB coding. Only TRα1, TRβ1, TRβ2 and TRβ3 bind to the ligand T3. Although TRα2 and TRα3 do not have the ability to bind to T3, they have antagonistic effects. In addition, the distribution of different isomers of TRs is structurally specific. TRαl and TRβ1 are expressed in almost all tissues, among which TRα1 is highly expressed in skeletal muscle, heart and brown adipose tissue, while TRβ1 is expressed more in liver and kidney. The expression of TRβ2 is very specific, and is mainly expressed in the anterior pituitary and hypothalamus, and is also expressed in the development of the brain and inner ear. TRβ3 is mainly expressed in the kidney, liver, and lungs. The specific distribution of different TR isoforms in tissues helps TR perform different functions in various tissues

Thyroid hormone signaling pathway

  1. Thyroid hormone signaling cascade

    The signaling pathway for thyroid hormone, triggered by the binding of thyroid hormone to the thyroxine hormone receptor, initiates a subsequent response and is regulated by several factors. To date, although many genes have been shown to be regulated by TH, only promoters of less than 30 genes contain TRE. With the application of deep sequencing in chip-on-chip analysis, a recent study showed that AMPK activity in the central nervous system is regulated by TH, but the authors did not indicate whether this regulation is a non-genomic effect of TH. In addition to the AMPK signaling pathway, the MAPK, PI3K, and AKT signaling pathways have been shown to be regulated by TH. Unlike some other nuclear receptors, TR regulates transcription either by forming homodimers or by forming heterodimers. Since there is a heterodimeric regulation, it can be inferred that the transcriptional activity of TR can also be regulated by the partner with which it forms a heterodimer. In vitro experiments have shown that heterodimers of RXR and TR significantly increase the ability of TR to bind TREs and promote transcription. In addition to RXR, other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) and vitamin D receptors (VDRs), have also been shown to form heterodimers as partners of TR. The D-box formed by the three amino acids of the DBD of TR has been shown to be an essential component in the formation of heterodimers, which are responsible for the isomer-dependent protein interactions as well as the specificity of the DNA binding sequences. Thus, the formation of heterodimers not only provides an alternative to the regulation of TR, but also provides a way for TR to interact with other nuclear receptors. Animal studies show that thyroid hormones play a biological role mainly by binding to TR and TR-α in knockout mice. Liver insulin sensitivity is improved in the body, and hepatic gluconeogenesis is inhibited. Feng et al used T3 to treat hypothyroidism mice labeled with fluorescent dyes, and analyzed them by cDNA microarray. The results showed that various genes are involved in hepatic glucose metabolism and insulin signal transduction: 1) Glucose-6-phosphatase mRNA expression is increasingly expressed, and the enzyme hydrolyzes glucose 6-phosphate to promote gluconeogenesis and glycogenolysis. 2) Protein kinase Akt2 is a serine/threonine kinase essential for the insulin signaling pathway and promotes hepatic glycogen synthesis by reducing the activity of glycogen synthase kinase 3 (GSK3). T3 can reduce the level of Akt2, reduce the inhibition of GSK3, reduce the synthesis of hepatic glycogen, and restore the activity of GSK3. Phosphorylation of insulin receptor substrate-1 leads to a decrease in insulin receptor signal, and the liver exhibits insulin antagonism. 3) T3 can also induce an increase in the expression of β2-adrenergic receptor mRNA and weaken the inhibitory effect of inhibitory Gi protein RNA on the adenylate cyclase cascade, thereby increasing gluconeogenesis and glycogenolysis. In addition, T3 can also upregulate some of the hepatic gluconeogenesis enzymes, including phosphoenolpyruvate and pyruvate carboxylase. Thyroid hormone can also increase hepatic glucose output and reduce hepatic glycogen synthesis by increasing the expression of glucose transporter 2 (GLUT2) on the liver cell membrane. The blood glucose in the GLUT2 knockout mouse liver cells is significantly increased, and the insulin blood is relatively low. Free fatty acids in the disease and circulation is high. At the same time, thyroid hormone can enhance the transfer of Akt phosphorylation (an important step in the insulin signal transduction cascade) and vesicle-associated membrane protein 2 (regulatory role in GLUT4 translocation) on 3T3-L1 adipocytes, thereby promoting GLUT4 transport and increasing glucose uptake after insulin stimulation. Similarly, T3 was also observed to increase expression GLUT4 in differentiated rat brown adipocytes. In human adipocytes, T3 can reduce the mRNA level of β2-AR in adipocytes, enhance the decomposition of catecholamine-induced lipolysis, and affect the formation of insulin by the following sterol regulatory element binding protein 1c. In skeletal muscle, thyroid hormone deficiency leads to abnormal regulation of mitochondrial gene expression. In addition, the low expression of type 2 iodized thymidine deiodinase (D2) plays a key role in the conversion of muscle T4 to T3 and the thyroid hormone amplification signal transduction pathway in cells, which is associated with insulin resistance. D2 enzymatic reaction-related factor studies have also shown that bile acids play an important role in thyroid hormone and glucose metabolism, which can improve insulin resistance.

  2. Thyroid hormone signaling pathway regulation

    The thyroid hormone response element (TRE) can be divided into two categories: positive and negative. Ligand-bound TR activates transcription by positive TRE and inhibits transcription by negative TRE. In contrast to a forward-regulated target gene, the transcriptional activity of a negatively regulated gene can be activated upon TH deletion and reduction. The DBD of TR plays an important role in DNA binding to a forward target gene. But does not play an important role in a negative T3 regulated target gene. TR does not depend on its ability to bind DNA in regulating the role of a negative target gene. It remains unclear whether TR binding DNA is necessary for negative regulation.Since TR binds slightly to the TREs of these genes, it is not known whether TR regulation is direct TR binding or protein interaction with other factors.

  3. Relationship with disease

    Hyperthyroidism

    Fasting hyperinsulinemia is very common in studies of hyperthyroidism. Animal studies have shown elevated plasma glucose and insulin levels in hyperthyroid animals. This is due to an increase in hepatic glucose, including increased gluconeogenesis, accelerated glycogenolysis, and reduced blood glucose clearance and processing capacity. In Grave's patients with hyperthyroidism, glucose tolerance is impaired. Hyperthyroidism is associated with elevated glucagon and increased growth hormone secretion, which also increases blood glucose levels and reduces glucose tolerance. A further comprehensive metabolic assessment showed that hyperthyroidism is characterized by hyperinsulinemia after oral glucose, as well as increased basal hepatic glucose production, insulin impaired ability to inhibit hepatic glucose production and insulin-stimulated peripheral glucose utilization.

    Hypothyroidism

    Hepatic glucose production is reduced in animals with hypothyroidism compared with hyperthyroidism. However, rodent hypothyroidism is accompanied by insulin resistance, which may be due to a decrease in glucose utilization and turnover in skeletal muscle and adipose tissue. However, the results of insulin sensitivity studies in patients with hypothyroidism are controversial.

    Thyroid hormone resistance

    In patients with thyroid hormone resistance syndrome (RTH), the level of free fatty acids in the blood increases, and the accumulation of triglyceride (TG) and diglyceride (DAG) in the muscle also increases. Recent studies have shown that homeostatic model assessment of insulin resistance (HOMA-IR) in patients with RTH is significantly higher than in the control group, and systemic insulin sensitivity is reduced. In patients with intracellular lipid intramyocellular lipid (IMCL) higher RTH, insulin sensitivity index is also often expressed in response to cholesterol-to-bile acid conversion and bile acid efflux.

References:

  1. Zhao L, Liu L, Wang S, et al. Transcriptome profiles of metamorphosis in the ornamented pygmy frog Microhyla fissipes clarify the functions of thyroid hormone receptors in metamorphosis. Sci Rep. 2016, 6:27310.
  2. Cohen K, Ellis M, Khoury S, et al. Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvβ3 integrin. Molecular Cancer Research Mcr. 2011, 9(10):1385-94.
  3. Napolitano F, D'Angelo L, Girolamo P D, et al. The Thyroid-target gene Rhes, a novel crossroad for neurological and psychiatric disorders: new insights from animal models. Neuroscience. 2018.
  4. Ghassabian A, Trasande L. Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine-Disrupting Chemicals on Child Neurodevelopment. Frontiers in Endocrinology. 2018, 9(5).
  5. Senger N, Melo M B, Diniz G P, et al. Angiotensin-(1-7) reduces cardiac effects of thyroid hormone by GSK3Β/NFATc3 signaling pathway. Clinical Science. 2018, 132(11):CS20171606.

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