Review Article Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases

Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 601361, 16 pages http://dx.doi.org/10.1155/2013/601361 Review Article Molecular Functions of Thyroid Hormones and Their Clinical Significance in Liver-Related Diseases Hsiang Cheng Chi,1 Cheng-Yi Chen,1 Ming-Ming Tsai,2 Chung-Ying Tsai,1 and Kwang-Huei Lin1 1 Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan 2 Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan Correspondence should be addressed to Kwang-Huei Lin; [email protected] Received 4 February 2013; Revised 14 May 2013; Accepted 28 May 2013 Academic Editor: Elena Orlova Copyright © 2013 Hsiang Cheng Chi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine3 (T ) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3 via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3 stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3 analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms. 1. Introduction play important roles in the pathogenesis of hepatocellular carcinoma (HCC). For instance, v-erbA, a mutant form of Thyroid hormones (THs), particularly triiodothyronine (T3), TR lacking ligand-binding ability, triggers HCC development are potent regulators of multiple physiological activities, in transgenic mice [19, 20]. Moreover, our group and other including cellular metabolic rate, heart and digestive func- researchers have shown that cloned TR and TR genes are tions, muscle function, brain development, and bone mainte- truncated or mutated at high frequencies in human HCCs nance [1, 2]. In addition to their crucial roles in maintaining [21–23]. Several groups, including ours, have focused on cellular homeostasis, THs can cause multiple disorders, the roles of T3 and TRs in liver disease, especially liver including cardiovascular disease [3, 4], diabetes mellitus [5, cancer. DNA microarrays have been widely employed to 6], and chronic liver disease [7–9], when their levels in the identify genes regulated by T3 in hepatoma cell lines and body are out of balance. The liver is a typical target organ provideaneffectivemeansforelucidatingtherolesofT3/TRs of THs. Equal amounts of thyroid hormone receptor 1 in human HCC. The results obtained to date collectively and 1 (TR1andTR1) proteins are expressed in human indicate that T3 andTRinfluencehepatomacellgrowth, hepatocytes [10]. Earlier studies reported that treatment with metabolism, apoptosis, and metastasis [23–28], suggesting T3 analogspreventshepaticsteatosisandhepatitis[11–16]. powerful therapeutic potential in clinical applications [29]. Additionally, THs have potential therapeutic applications in In the current report, we review studies by our research hepatitis B and C [17, 18]. Interestingly, T3 and TRs also group and other investigators on the roles of THs and TRs 2 BioMed Research International in liver diseases, particularly HCC. Elucidating the molecular abundant in testis and skeletal muscle [43]. Interestingly, basisfortheeffectsofT3/TR on hepatocytes and hepatoma whereas human TR1, TR2, and TR1areabundantin may facilitate the design of improved strategies for preventing different tissues, none is highly expressed in the liver, the or curing liver-related diseases ranging from steatosis to major TH target organ [38]. HCC. 2.2. Transcriptional Activities of T3/TRs. The protein struc- 2. Actions of Thyroid Hormones and tureofTRs,similartothatofothernuclearreceptors,contains Thyroid Hormone Receptors modular functional domains, including an N-terminal A/B domain, a DNA-binding domain that recognizes TREs within The physiological actions of THs affect almost every organ thetargetgenepromoter,ahingeregion(D),andaC- system. Clinically, these effects are observed as changes in terminal ligand-binding domain (E) responsible for dimer- metabolic rate, altered lipid metabolism, and characteristic ization with other nuclear receptors or interactions with effects on cardiovascular development30 [ –32]. Under phys- transcriptional coregulators [36, 44–47]. The TR exerts its iological conditions, T4 is the main hormone secreted into transcriptional activity as a homodimer or as a heterodimer the bloodstream by the thyroid gland. Conversion of T4 with other nuclear receptors, including retinoid X receptor tothemoreactiveform,T3, is regulated in extrathyroidal (RXR) and other retinoic acid receptor subtypes, and vitamin tissue through the selenoprotein enzyme system. Expression D receptors (VDR). RXR is the general partner of several levels and activities of type I and type II deiodinases (D1 nuclear receptors in the regulation of target genes [48]. TRs and D2) vary among tissues, leading to tissue-specific dif- generally heterodimerize with RXRs and localize to TREs ferences in the levels of circulating T3 andactivehormone within the promoter regions of target genes (Figure 1(a)). available for binding to nuclear receptors. Conversely, type The TR/RXR heterodimer exhibits the highest T3 binding III deiodinase (D3), which converts T4 and T3 to the affinity and remains stable during ligand binding. The known comparatively inactive forms, reverse triiodothyronine (rT3) requirement of RXR for maximal transcriptional activation and 3,3 -diiodothyronine (T2), respectively, is responsible for by TRs highlights the crucial role of these interactions [49, suppression of hormone activity [33]. Both T3 and T4 act via 50]. TRs. However, the TR binding affinity of T4 is considerably TREs within promoter regions of T3 target genes gener- lower than that for T3. According to the genomic action of ally contain a core consensus “half-site” with the sequence thyroid hormone, T3 bindingwithTRslocatedonthyroid (A/G)GGT(C/A/G)A. A typical TRE contains two half-site hormone response elements (TREs) of promoter regions sequences in palindromic, direct-repeat, or inverted-repeat induces target gene expression at the transcriptional level arrangements that are recognized by TRs (Figure 1(a)) [45]. [20, 34, 35]. In the absence of T3,TRsusuallyactastranscriptional repressors. Upon T3 binding, TRs undergo a conformational 2.1. Thyroid Hormone Receptors. TRs belong to the nuclear change that causes dissociation of their corepressors, such as receptor superfamily and act as T3-inducible transcription nuclear receptor corepressor (NCoR) or itshomolog silencing factors. TRs are encoded by two genes, THRA and THRB, mediator of retinoic and thyroid receptor (SMRT), allowing locatedatseparateloci[36]. The THRA gene, located on induction of target gene expression (Figure 1(a)). NCoR chromosome 17, encodes one functional T3-binding TR1 and SMRT corepressor-mediated TR functions have been and two dominant-negative splice variants, TR2andTR3 extensively characterized [36]. Specifically, NCoR and SMRT [37], that lack T3 binding ability [38]. TRΔ1andTRΔ2 display histone deacetylase activity and serve as a platform for are truncated variants transcribed from an internal promoter repressor complex-mediated chromatin remodeling. In addi- locatedwithinintron7.ThesetruncatedformslackDNA- tion, both corepressors are associated with histone deacety- binding domains, but retain T3-binding competence [39]. lase 3 (HDAC3) and other proteins, such as transducin-like TR1andTR2 are highly expressed in the brain, with lower protein (TBL1), forming large repressor complexes [51]that abundanceinthekidneys,skeletalmuscle,lungs,heart,and suppress transcription via activation of HDAC3 or TBL1. testes [40]. The conformational change in TRs induced by T3 binding THRBgenesarelocatedonchromosome3andencode leads to the recruitment of transcriptional coactivators of three functional T3-binding TR isoforms (1, 2, and 3) target gene transcription. The steroid hormone receptor [37]. Interestingly, the truncated TR variant, TRΔ3, lacks coactivator (SRC) and p160 family members that interact with the DNA-binding domain but retains T3 binding activity and ligand-bound TR to facilitate activation of T3 target genes acts as a dominant-negative antagonist [37]. TR1iswidely are well characterized [52]. SRC-1 utilizes its histone acetyl- expressed in all tissues, but is particularly prominent

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