Thyroid Hormone Receptor Coregulators in Metabolic Regulation

It has been known for a long time that thyroid hormone regulates metabolism. Thyroid hormone action is primarily mediated by Thyroid Hormone Receptors (TRs). The transcriptional regulation by TRs is modulated by coregulators including coactivators and corepressors. Emerging evidence suggested that coregulators are critical for metabolic regulation mediated by TR. This review describes recent in vivo findings that improve our understanding of the roles of coregulators and provides an alternative way to enhance our knowledge on TR-mediated metabolic regulation. In order to delineate the complex mechanisms involved, we compare the results obtained from the researches employing different lines of mouse genetically modified. It is found that both corepressors and coactivators are indispensible for the full function of TR. We also discuss the challenge and future direction in the research field of thyroid hormone action in metabolism. THYROID HORMONE AND THYROID HORMONE RECEPTOR The active form of thyroid hormones (TH), 3,3’5-Triiodol-Thyronine (T3), play critical roles in growth, development, differentiation, and metabolism [1-5]. The circulating TH levels are tightly controlled by hypothalamic-pituitary-thyroid (HPT) axis, while the local TH levels are regulated by deiodinaseisozymes [6]. Many of the effects of TH are mediated by TH Receptors (TRs), which are ligand-inducible transcription factors that belong to nuclear receptor (NR) super family [4,7,8]. TH is able to positively regulate the expression of many target genes. In the absence of T3, TRs constitutively interact with Thyroid Response Element (TREs) in the promoter region of target genes and inhibit the basal transcription; in the presence of T3, T3 binds to TRs, resulting in conformation change of TR and transcriptional activation [4,8]. TH also inhibits gene expression in the presence of T3, the mechanisms of which is not well understood [9-11]. There are three major hormone binding TRs, TRβ1, TRβ2, and TRα1, which are encoded by two genes. Like other classical NRs, these major TR isoforms contain three major domains including A/B domain, DNA-Binding Domain (DBD), and LigandBinding Domain (LBD). A long-standing question in the research of TR is whether these isoforms have divergent functions. Targeted deletion or mutation of the TRα or TRβ genes in mice has shown that TR isoforms could play specific or overlapping roles depending on certain circumstances [12,13]. This complex way of regulation may be partly ascribed to the tissue-specific expression and/or receptor-specific activity of different TR isoforms [14]. Although it is well reckoned that different TR isoform exerts distinct function, the molecular mechanisms involved still remain to be elucidated. TH-REGULATED GENES INVOLVED IN METABOLIC REGULATION At transcription level, abundant key players involved in energy homeostasis, carbohydrate and lipid metabolism have been reported to be under the direct or indirect control of TH and TR. For instance, TR has been proved to positively regulate the expression of brown adipose tissue-specific Uncoupling Protein 1 (UCP1), ubiquitously expressed UCP2, and skeletal muscle enriched UCP3, which might explain one of the potent role of TR in the regulation of basal metabolic rate and energy expenditure [15]. Glucose transporter type 4 (GLUT4) and gluconeogenic Phosphoenolpyruvate Carboxy Kinase (PEPCK) expression are alsopositively regulated by TH, suggesting that TH increase glucose uptake and enhance glucose production in muscle and liver, respectively [16,17]. TR also regulates Special Issue on Role of Thyroid Hormone in Metabolic Homeostasis Central Ying et al. (2014) Email: J Endocrinol Diabetes Obes 2(3): 1051 (2014) 2/7 mitochondrial glycerol-3-phosphatedehydrogenase gene (Gpd2), which is critical for glycerol production and serves as a major link between carbohydrate metabolism and lipid metabolism [18]. In liver, lipogenic genes such as Fatty Acid Synthase (FAS), Thyroid Hormone Responsive Spot 14 (THRSP), Malic Enzyme (ME), and acetyl-CoA-carboxylase (ACC) are positively regulated by TH, while pro-lipogenicstearoyl-CoA desaturase-1 (SCD1) is negatively regulated by TH [19-23]. In addition, hepatic carnitine palmitoyl transferase 1α (CPT1α), a rate-limiting enzyme for fatty-acyl-CoA transport and β-oxidation in the mitochondria, is a target gene positively regulated by TH [24]. Genes involved in cholesterol metabolism are also regulated by TRs such as, cholesterol 7a-hydroxylase (CYP7A), HMG-CoA Reductase (HMGCR), Low Density Lipoprotein Receptor (LDLR), and scavenger receptor class B member 1 (SR-B1) [25-27]. CYP7A controls cholesterol catabolism and bile acid synthesis. HMGCR determines the rate of cholesterol biosynthesis. LDLR and SRB1 are involved in cholesterol uptake. It can be seen that genes involved in cholesterol synthesis and disposal are both controlled by TRs. The net effect of TH on cholesterol homeostasis might depend on the coordinated activity of these enzymes or receptors [27]. Adipose tissue metabolism is also well regulated by TRs. In addition to promote adipogenesis by regulating C/EBPα expression, TH increases lipolysis and the released fatty acid is delivered to liver and muscles for oxidation [4,8]. Collectively, TH and TR play pleiotropic roles in regulating metabolism and maintaining homeostasis. NUCLEAR RECEPTOR COREGULATORS The transcriptional activity of TRs is controlled through multiple ways. An NR coregulator, including coactivators and corepressors, has been shown to play important roles in modulating TR-mediated transcription [28]. These coregulators and the complexes consisting of them have undertaken roles including altering chromatin structure and contacting the basal transcription machinery [7,8]. Nuclear receptor corepressor (NCoR) and Silencing Mediator of Retinoid and Thyroid receptors (SMRT) are two of the well studied corepressors involved in TR function. NCoR and SMRT were described as prototypical NR corepressors [29]. TRs bind with NCoR with higher affinity than SMRT, and thus NCoR is believed to preferentially control transcription repression mediated by TR. In the absence of T3, NCoRor SMRT forms a complex with Histone Deacetylase 3 (HDAC3) and is recruited by TR to the promoter region of target genes to suppress transcription [30]. In the presence of T3, T3bound TR disassociates corepressor complexes and recruits coactivator complexes with histone acetyl transferase activity to activate transcription [28,31]. Similar to that of TR isoforms, the activity of coregulators is spatially and temporally regulated, which coordinates with the regulation of TR isoform to achieve their selective functions [32-35]. Thus, the recruitment of different co-regulator complexes provides another layer in the transcriptional regulation by TH [35-38]. THYROID HORMONE RECEPTOR COREGULATORS AND METABOLISM Emerging in vivo evidence suggests that NR coregulators are involved in diverse aspects of metabolic regulation. However, distinct coregulators might selectively bind to different NRs. Meanwhile, one target gene could be simultaneously controlled by multiple NRs. These innate complexities of regulation render us difficult to interpret the data obtained from individual genetic manipulated mouse model targeting the coregulator. Thus it is worthwhile to review the in vivo researches in recent days so as to help us better understanding the role of NCoR, SMRT, as well as other regulators on TR-regulated gene expression and metabolism, especially in the liver. We also apologize to all the researchers which have contributed to the field but are not cited here.