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Thyroid hormone action

Thyroid hormone action
Author:
Gregory A Brent, MD
Section Editor:
Douglas S Ross, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jan 2024.
This topic last updated: Apr 27, 2022.

INTRODUCTION — Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults; they also affect the function of virtually every organ system. Thyroid hormones must be constantly available to perform these functions. To maintain their availability, there are large stores of thyroid hormone in the thyroid gland. Furthermore, thyroid hormone biosynthesis and secretion are maintained within narrow limits by a regulatory mechanism that is very sensitive to small changes in circulating hormone concentrations.

Thyroid hormone, in the form of triiodothyronine (T3), acts by modifying gene transcription in virtually all tissues to alter rates of protein synthesis and substrate turnover [1,2]. These actions are the net result of the presence of T3 and of multiple other factors that amplify or reduce its action (figure 1A-B). Thyroid hormone action is recognized to occur by direct binding of thyroid hormone receptor (TR) to DNA, referred to as Type 1, but can be due to indirect binding of TR to DNA (type 2) or even without DNA binding (type 3) [3]. Extranuclear actions of T4 and T3 have been increasingly recognized and are mediated by interactions with membranes receptors, organelles, and components of the signal transduction system (type 4) [4].

The actions of T3 will be reviewed here. The production of T3 and its precursor thyroxine (T4) and how their production is regulated are discussed elsewhere. (See "Thyroid hormone synthesis and physiology".)

DETERMINANTS OF T3 ACTION — The nuclear actions of triiodothyronine (T3) are dependent upon four factors: the availability of the hormone, thyroid hormone nuclear receptors (TRs), receptor cofactors, and DNA regulatory elements.

Ligand availability — Thyroid hormone synthesis and secretion from the thyroid gland are regulated by pituitary thyroid-stimulating hormone (TSH) (see "Thyroid hormone synthesis and physiology"). Circulating T4 and T3 enter cells by diffusion and, in some tissues, such as the thyroid and brain, by active transport [5]. An inherited defect in the MCT8 thyroid transporter has been associated with alterations of circulating thyroid hormone levels, due to reduced transport of thyroid hormone out of the thyroid [6], and severely impaired neurologic development in boys, due to reduced transport of T3 into neurons [5].

T3 is also available to cells because it is produced from T4 within them. The locally produced T3, some of which leaves the cells, provides much of the T3 that is bound to T3 nuclear receptors in many tissues. Overall, approximately 80 percent of circulating T3 in humans is derived from extrathyroidal conversion of T4 to T3 and approximately 20 percent from direct thyroidal secretion [7].

The regulation of T3 production at the tissue level is increasingly recognized as an important influence on thyroid hormone action. The fraction of T3 that is produced locally from T4, and the contribution of locally produced T3 to the amount of T3 bound to its receptors vary substantially by species and from tissue to tissue [8]. In humans, approximately 80 percent of extrathyroidal T3 produced from T4 is produced intracellularly [7,8].

Thyroid hormone nuclear receptors — There are two TRs, alpha and beta (figure 2) [1,2]. They are encoded by separate genes located respectively on chromosomes 17 and 3 (referred to as THRA and THRB, respectively). TR-alpha and -beta are structurally similar; as a result of alternative splicing, there are multiple forms of each, TR-alpha-1 and 2 and TR-beta-1, 2, and 3. T3 binds to these TRs, with the exception of TR-alpha-2, and the T3-TR complexes then bind to regulatory regions contained in the genes that are responsive to thyroid hormone (figure 1A and figure 1B). TRs without T3 bind to nuclear receptor corepressors and then to regulatory regions of genes normally induced by T3, resulting in repression of gene expression.

The TR isoforms contain separate domains that bind T3, DNA, and form dimers with TR molecules, as well as other receptors such as retinoid X receptors (RXRs), which bind 9-cis retinoic acid (figure 2) [9]. The predominant functional unit for T3 gene regulation is a TR/RXR heterodimer (figure 1A and figure 1B). The influence of RXR on the nuclear receptor complex varies depending on its receptor partner, but thyroid hormone is the major influence on the activity of the TR/RXR heterodimer [9].

Receptor cofactors — There is a large family of regulatory proteins that interact directly with TR to augment or inhibit the response to T3. (See 'TR cofactors' below.)

DNA regulatory elements — The 5'-flanking region (located upstream of the transcription start site) of thyroid hormone-responsive genes contains specific DNA sequences that bind TR/RXR heterodimers, thereby altering gene expression.

THYROID HORMONE ACTIONS DURING DEVELOPMENT — Thyroid hormone has important effects on neural and somatic development, both during fetal life and the first years of postnatal life.

Ligand availability during fetal development — The fetal thyroid gland begins to function at 10 to 12 weeks of gestation, and it is the primary source of thyroid hormone in the developing fetus after the first trimester, during which maternal T4 is the only source. In congenital hypothyroidism, where the fetus makes no thyroid hormone, sufficient maternal T4 crosses the placenta to the fetus for normal in utero development (or nearly so) [10]. In severe iodine deficiency, which is associated with both maternal and fetal hypothyroidism, fetal development is not normal, and the changes are not reversible with postnatal thyroid hormone therapy. Women who are hypothyroid during pregnancy have an increased risk of miscarriage and preterm delivery and some mild intellectual impairment in their offspring [11]. (See "Overview of thyroid disease and pregnancy", section on 'Hypothyroidism during pregnancy' and "Thyroid physiology and screening in preterm infants".)

Expression pattern of TR isoforms — The pattern of thyroid hormone receptor (TR)-isoform expression is similar among the different species in which it has been studied, and it differs in fetal and adult tissues (figure 3). TR-alpha is expressed first. TR-beta appears later, usually detected at the time T3 is first produced. Both TR-alpha and beta are functional, although the timing and pattern of expression suggest specific roles in development. (See 'Tissue-specific expression of TR isoforms' below.)

TISSUE-SPECIFIC THYROID HORMONE ACTION — T3 has different actions in different tissues. These differences are determined by variations in both local production of T3 and the tissue distribution and content of thyroid hormone receptor (TR) isoforms [1,2].

Tissue-specific expression of TR isoforms — The variable expression of the isoforms of TR-alpha and beta in tissues has been characterized (figure 3) [1,12]. Liver, muscle, and kidney contain predominantly TR-beta, whereas the heart contains similar amounts of TR-alpha and beta. The brain contains predominantly TR-alpha, but TR-beta-2 is present in high levels in some areas of the brain, especially in the hypothalamus and pituitary, and it has a special role in regulation of genes negatively regulated by T3, such as the genes for thyrotropin-releasing hormone (TRH) and the subunits of thyroid-stimulating hormone (TSH). Even within a tissue (as an example, bone, heart, or brain) there is region- or cell-specific distribution of TR isoforms, suggesting that the different TR isoforms have different functions.

Most of what is known about the role of the individual TR isoforms comes from gene-deletion (knockout) and TR gene point mutation studies in mice (table 1), as well as the human syndromes of resistance to thyroid hormone. In these studies, mice are created from embryonic stem cells in which the TR-alpha or beta gene is deleted or mutated and the resulting mice have the abnormality. The function of the gene is determined based on the phenotype of the genetically altered mice as compared with normal (wild-type) mice [1], as well as the influence of cofactors [13].

TR-alpha gene knockout and point mutation mice – Mice with TR-alpha deletion have poor feeding and growth, reduced bone mineralization, low basal body temperature, and slowed heart rate. Changes in thyroid function include low serum TSH and T4 concentrations. Mice heterozygous for dominant negative point mutations, analogous to those identified in TR-beta gene associated with resistance to thyroid hormone, have a phenotype generally similar to the TR-alpha homozygous deletions [14]. Additional abnormalities that have been reported in mice with dominant negative TR-alpha mutations include defects in neurologic development, impaired adaptive thermogenesis and, in one TR-alpha mutation, obesity and impaired lipolysis [1]. Families with resistance to thyroid hormone associated with mutations in the TR-alpha gene have been reported [15]. These patients have low serum T4, normal or elevated serum T3, and normal to elevated serum TSH, with signs of hypothyroidism including abnormal bone development, constipation, and signs of reduced metabolism. (See "Resistance to thyroid hormone and other defects in thyroid hormone action", section on 'Resistance to thyroid hormone alpha (RTH-alpha)'.)

TR-beta gene knockout and point mutation mice – Inactivation of the TR-beta gene is associated with thyroid-gland hyperplasia, high serum T4 concentrations, and inappropriately normal serum TSH concentrations [1,2], similar to the clinical features of patients with resistance to thyroid hormone associated with a TR-beta gene mutation (see "Resistance to thyroid hormone and other defects in thyroid hormone action", section on 'RTH-beta'). Other findings include hearing loss, which correlates well with the expression of TR-beta in the developing cochlea in normal mice, and tachycardia. Survival is normal. Mice heterozygous for point mutations in the TR-beta gene, modeled after those seen in resistance to thyroid hormone, have a similar phenotype to mice homozygous for TR-beta deletion.

Both TSH secretion in response to hypothyroidism and T3 suppression of TSH secretion is impaired in these mice. These results indicate that TR-beta plays an important role in ligand-independent increase and T3-mediated suppression of TSH.

Combined TR-alpha and beta knockout mice – Mice in which both TR-alpha and beta genes are deleted have marked thyroid hyperplasia and high serum concentrations of T4 (11 times greater than normal), T3 (30 times greater than normal), and TSH (up to 160 times greater than normal) [16]. They grow poorly, the pituitary content of growth hormone mRNA and growth hormone is low, and they have low serum insulin-like growth factor-1 (IGF-1) concentrations. Bone development and mineralization are defective, and the epiphyseal plates are disorganized. Fertility is severely impaired in the females. Lifespan is reduced; approximately 30 percent of the mice die by nine months of age, as compared with no deaths among wild-type mice at this age.

Important target tissues for thyroid hormone during development include bone, pituitary, small intestine, retina, and the inner ear (table 2).

TR cofactors — Gene activation or repression mediated by TRs also involves the interactions of TRs with other protein cofactors [13]. These proteins, termed coactivators and corepressors, promote or impair interaction of TR with the basal transcription machinery (figure 1A-B). Many of these cofactors interact with steroid hormone and retinoid receptors in addition to TRs. Examples of coactivators are SRC (steroid receptor coactivator) and CBP (CREB [cAMP response element-binding protein]-binding protein). Examples of corepressors are NCoR (nuclear corepressor) and SMRT (silencing mediator of retinoid and thyroid receptors).

In general, corepressors bind to TR in the absence of T3 and repress gene expression. T3 binding to TR displaces corepressor bound to TR and promotes binding of coactivator to promote gene activation. The TR mutations associated with thyroid hormone resistance generally result in irreversible interactions with corepressors that are not displaced by the addition of ligand, T3. In mouse models of resistance to thyroid hormone with a TR-beta gene mutation, crossing with a mouse expressing a mutant NCoR that does not bind to TR results in a partial "rescue" of the resistance phenotype. This finding suggests that irreversible binding of corepressor to the mutant TR is an important mechanism of the thyroid hormone resistance phenotype [13].

The results of animal and human studies suggest that these receptor coactivators and corepressors play essential roles in development and hormone action. Knockout of the SRC and CBP genes is lethal in fetal or neonatal life. These findings indicate the essential nature of these cofactors for development, but they do not provide information on what genes are most affected when the cofactors are absent. An example of the role of a cofactor in thyroid hormone regulation is SRC. Mice with SRC gene deletion have high serum TSH and T4 concentrations, which increase readily in response to hypothyroidism, but do not decrease normally in response to exogenous T3 [13].

Approximately 10 percent of patients with the typical clinical features of thyroid hormone resistance do not have TR mutations and may have cofactor gene mutations [17]. (See "Resistance to thyroid hormone and other defects in thyroid hormone action", section on 'NonTR-RTH'.)

DNA response elements — All genes regulated by T3 have specific sequences of DNA that bind TR with high affinity [1,2]. Most of these sequences, known as thyroid hormone-response elements, consist of two tandemly arranged hexamer (or octamer) motifs with a consensus sequence of AGGTCA to which T3-TR/retinoid X receptor (RXR) heterodimers bind, separated by four base pairs. Response elements are contained in the 5'-flanking regulatory region of the gene, but they can be located throughout the gene including in introns and flanking sequences.

The configurations of response elements that confer T3-dependent gene activation have been well characterized and preferentially bind T3-TR/RXR heterodimers. A single octameric sequence, TAAGGTCA, can also bind TR-TR dimers and confer positive gene regulation [1,2]. Response elements that mediate gene repression have been more difficult to identify, and some appear to bind only T3-TR monomers. It is likely that negative regulation involves interaction with other transcription factors.

In all genes transcriptionally regulated by T3, it should be possible to identify a DNA sequence that confers this regulation. With the availability of DNA sequence data from the human genome project, it is possible to identify T3-regulated genes based upon sequence inspection. Direct approaches to screen for sequences that bind receptors are available and have been utilized to identify genes regulated by related hormones, such as estrogen.

Tissue-specific expression of thyroid hormone deiodinases — The deiodinases that convert the prohormone T4 to the active hormone T3 and convert T3 to diiodothyronines are expressed in a development- and tissue-specific pattern [7,8]. (See "Thyroid hormone synthesis and physiology".)

Type 1 5'-deiodinase (Dio1) is expressed predominantly in liver, kidneys, and muscle. In rodents, this enzyme is the primary source of circulating T3. Dio1 activity is reduced in hypothyroidism.

Type 2 5'-deiodinase (Dio2) is expressed primarily in brown fat, pituitary, and cerebral cortex in rodents. It is more widely expressed in humans, including the thyroid, heart, and skeletal muscle, and produces the majority of circulating T3 in humans. Dio2 activity is increased in hypothyroidism and iodine deficiency.

Type 3 5-deiodinase (Dio3) inactivates T4 and is expressed in placenta, developing brain, skeletal muscle, and skin. Developmentally, this is the first deiodinase expressed, and expression falls as expression of the other two deiodinases increases. Dio3 activity is also important to balance thyroid hormone action in sensory development, especially of the inner ear.

Dio3 appears to play a critical role in the maturation and function of the thyroid axis. This was illustrated by a Dio3-knockout mouse model where neonatal thyrotoxicosis followed by central hypothyroidism was observed [18].

THYROID HORMONE ACTION IN BONE, HEART, AND REGULATION OF METABOLISM — Major targets of thyroid hormone are the skeleton, the heart, and the metabolic regulation.

Bone and bone development — Infants with congenital hypothyroidism who are not treated have disordered and delayed epiphyseal development and grow poorly, as do some infants with thyroid hormone resistance [19]. Abnormal bone development is also a major feature of thyroid hormone receptor (TR)-alpha and combined TR-alpha/beta-knockout mice (table 1) [20,21]. All TR isoforms are expressed in bone and probably interact with other nuclear receptors including those for vitamin D and retinoids [20,21].

Serum osteocalcin concentrations are correlated with thyroid status, and osteocalcin mRNA levels in bone are stimulated by T3 in a region-specific pattern, paralleling those areas such as the hip that are most susceptible to osteoporosis in patients with hyperthyroidism [21]. Thyroid hormone-mediated bone loss is the result of TR-alpha enhancement of catecholamine action. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)

Cardiac gene expression — The heart is a major target for thyroid hormone action [22]. Most patients with thyroid hormone resistance have tachycardia, indicating no cardiac resistance to T3. This observation is consistent with the fact that these patients have TR-beta mutations, and the atria contains primarily TR-alpha. Mice with TR-beta deletions do not show cardiac resistance to T3; however, mice with TR-alpha deletions have bradycardia [1]. This is also consistent with the absence of tachycardia in patients treated with selective TR-beta agonists [23].

Regulation of metabolism — Thyroid hormone regulates metabolic rate and is associated with modest changes in body weight [24]. Animal models have demonstrated that TR-alpha is important for thyroid hormone-mediated enhancement of adrenergic action [1,24]. Humans with thyroid hormone resistance associated with TR-beta mutations and elevated thyroid hormone levels have increased stimulation of TR-alpha. The metabolic phenotype of increased TR-alpha stimulation is increased feeding and increased fatty acid oxidation [25]. Human studies have shown a direct connection between thyroid status and response to adrenergic stimulation in subcutaneous fat [26]. The regulation of glucose uptake is more complex, but thyroid hormone promotes glucose uptake and polymorphisms in the type 2 5'-deiodinase (Dio2) gene have been associated with glucose intolerance [27]. Impairment of mitochondrial oxidative metabolism, as is seen in type 2 diabetes and the metabolic syndrome, may be linked in some individuals to reduced thyroid hormone action [28]. Thyroid hormone also regulates metabolism by interaction with other metabolic nuclear receptors such as peroxisome proliferator-activated receptor (PPAR)-alpha and liver X receptor (LXR) [3].

AGENTS THAT MAY INTERFERE WITH THYROID HORMONE ACTION — A range of drugs have been reported that can alter T4 absorption and metabolism [29]. Agonists for retinoic acid receptor (RAR) and retinoid X receptor (RXR), retinoids and rexinoids, suppress thyroid-stimulating hormone (TSH) and can produce central hypothyroidism in some patients [30]. Agents that have been shown to interfere with thyroid hormone action include smoking cigarettes [31] and a range of environmental agents, especially polychlorinated biphenyls (PCBs) [32]. Iodine is concentrated in the thyroid gland by the action of the sodium/iodide symporter (NIS) [33]. Agents that block NIS and iodine concentration include perchlorate, a contaminant of water and food in some regions, and thiocyanate, found in water and cigarette smoke [32,34]. Soy is frequently implicated, but there is no convincing evidence that soy protein or isoflavones interfere with thyroid hormone action in vivo [35]. Soy protein, however, can interfere with T4 absorption from the intestine, which is especially important for infants with congenital hypothyroidism on T4 replacement and receiving soy-based formula [35].

CLINICAL APPLICATIONS — The identification of development- and tissue-specific pathways of thyroid hormone action is being translated into novel therapies. As an example, identification of the crystal structure of the ligand-binding domain of thyroid hormone receptors (TRs) has led to synthesis of novel analogues that are potential treatments for a variety of conditions, including hypercholesterolemia, hepatic steatosis, obesity, and heart failure [23,36,37]. A highly innovative use of thyroid hormone is the topical application of T3, shown in animal models to accelerate wound healing [38].

Clinical markers of thyroid hormone action — The cornerstone of clinical assessment of thyroid status is measurement of serum thyroid-stimulating hormone (TSH). Although this is the gene product regulated by thyroid hormone that is most easily measured, this does not necessarily mean that the intensity of action of thyroid hormone in other tissues is similar. As discussed previously, the tissue distribution of deiodinases varies, which means that local production of T3 may vary. Thus, there is the potential for disparity of T3 production and therefore action in different tissues.

Other clinical markers of T3 action are serum sex hormone-binding globulin (SHBG), osteocalcin, and angiotensin-converting enzyme concentrations [23], all of which are increased by T3. Conversely, serum cholesterol concentrations are decreased by T3. However, none of these measurements is as sensitive to changes in serum T4 and T3 concentrations as are measurements of serum TSH. Based on animal studies, however, levels of gene products in specific thyroid hormone target tissues may give the best "profile" of tissue thyroid status, but this is not yet possible in humans [1].

Selective thyroid hormone analogs — Many analogs of T4 and T3 have been synthesized in the hope of finding one that would have a desired effect of thyroid hormone, such as lowering serum cholesterol concentrations or stimulating energy expenditure, without having undesirable effects on the heart, skeletal muscle, or bone. In hypothyroid patients given doses of T4 and triiodothyroacetic acid (tiratricol) that have similar effects on TSH secretion, triiodothyroacetic acid resulted in lower serum cholesterol and higher SHBG concentrations and greater increases in markers of bone formation and resorption, indicating some dissociation of effects on the pituitary, liver, and bone [39].

The identification of the crystal structure of the ligand-binding domain of TRs has led directly to the design of agonists that selectively stimulate TR isoforms [36,37]. As an example, sobetirome (also referred to as GC1), designed based on the crystal structure of the ligand-binding domain of the TRs, has a 10-fold higher affinity for TR-beta than for TR-alpha. In hypothyroid rats treated with equimolar doses of T3 or sobetirome, sobetirome caused a greater reduction in serum triglyceride concentrations, equivalent reduction in serum cholesterol concentrations, and less stimulation of the heart (as assessed by heart rate and cardiac-specific gene expression). Sobetirome is a potent "browning" agent, converting white fat to metabolically active brown fat in an obese mouse model and producing weight loss [40]. Thyroid hormone has been utilized in animal models and human studies as a treatment for nonalcoholic fatty liver disease (NAFLD) [41].

Hypercholesterolemic patients not at low-density lipoprotein (LDL) target levels while on statins were given eprotirome (KB2115), a TR-beta selective agonist. Treatment for 12 weeks resulted in reduced total and LDL cholesterol in all patients and also reduced triglycerides in those individuals with elevated baseline triglyceride levels [42]. Adverse effects on the heart or bone were not detected in this short study, although a transaminitis was seen in some patients and the levels of SHBG were significantly elevated. Expanded clinical trials with eprotirome are reviewed elsewhere. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Thyromimetics'.)

The vascular system is being increasingly recognized as a therapeutic target for thyroid hormone and its analogs [23,43]. A cardio-selective thyroid hormone analog, DITPA, has had some utility in treatment of congestive heart failure [44], although a longer study resulted in significant toxicity, especially metabolic with significant weight loss, and the trial was stopped [42,45].

The thyroid hormone analogs DITPA and TRIAC do not require MCT8 to enter neurons, as shown by treatment of animal models with MCT8 gene inactivation [46]. Although the neurologic defects in patients with Allan-Herndon-Dudley syndrome, the condition with an MCT8 transporter gene mutation and profound neurologic deficit, are not reversed by DITPA treatment, it did suppress TSH, reduce T3 levels, and reverse the hypermetabolism and weight loss [47]. A reversal of neurologic phenotype was demonstrated in an animal model of X-linked adrenoleukodystrophy, where treatment with sobetirome activates an alternative transporter for very long-chain fatty acids and partially reversed fat deposition in the brain and adrenals [48]. A central nervous system (CNS)-selective prodrug of sobetirome (Sob-AM2) has been shown to stimulate myelin production from oligodendrocytes and remyelinated an animal model of demyelination and improved motor function [49]. T3 has also been utilized in in vivo models of brain injury, showing that T3 treatment reduces brain edema, limits neuronal destruction, and promotes recovery [50].

SUMMARY — Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults; they also affect the function of virtually every organ system. Thyroid hormones must be constantly available to perform these functions.

Circulating thyroxine (T4) and triiodothyronine (T3) enter cells by diffusion and, in some tissues such as the brain, by active transport. T3 is also available to cells because it is produced from T4 within them. The locally produced T3, some of which leaves the cells, provides much of the T3 that is bound to T3 nuclear receptors in many tissues. Overall, approximately 80 percent of circulating T3 in humans is derived from extrathyroidal conversion of T4 to T3 and approximately 20 percent from direct thyroidal secretion. (See 'Ligand availability' above.)

There are two thyroid hormone nuclear receptors (TR), alpha and beta (figure 2). T3 binds to these TRs, and the T3-TR complexes then bind to regulatory regions contained in the genes that are responsive to thyroid hormone. TRs without T3 bind to nuclear receptor corepressors and then to regulatory regions of genes normally induced by T3, resulting in repression of gene expression (figure 1A and figure 1B). (See 'Thyroid hormone nuclear receptors' above.)

Thyroid hormone, in the form of T3, acts by modifying gene transcription in virtually all tissues to alter rates of protein synthesis and substrate turnover. T3 has different actions in different tissues. These differences are determined by variations in both local production of T3 and the tissue distribution and content of TR isoforms (table 2). The deiodinases that convert the prohormone T4 to the active hormone T3 and convert T3 to diiodothyronines are also expressed in a development- and tissue-specific pattern. (See 'Tissue-specific thyroid hormone action' above.)

Thyroid hormone has important effects on neural and somatic development, both during fetal life and the first years of postnatal life. Major targets of thyroid hormone are the skeleton, the heart, and the metabolic regulation. (See 'Thyroid hormone actions during development' above and 'Thyroid hormone action in bone, heart, and regulation of metabolism' above.)

The identification of development- and tissue-specific pathways of thyroid hormone action is being translated into novel therapies. As an example, identification of the crystal structure of the ligand-binding domain of TRs has led to synthesis of novel analogues that are potential treatments for a variety of conditions, including hypercholesterolemia, hepatic steatosis, obesity, heart failure, and neurologic disorders. (See 'Clinical applications' above.)

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Topic 7864 Version 13.0

References

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