143 REVIEW Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors Changxue Lu and Sheue-Yann Cheng Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264, USA (Correspondence should be addressed to S-Y Cheng; Email: [email protected]) Abstract Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. Journal of Molecular Endocrinology (2010) 44, 143–154 Introduction (NR1C3; Fig. 1), are encoded by three different genes (PPARA, PPARD, and PPARG) located at chromosomes Peroxisome proliferator-activated receptors (PPARs) 22, 6, and 3 respectively. Upon ligand binding, PPARs and thyroid hormone receptors (TRs) are ligand- are recruited to peroxisome proliferator response dependent transcription receptors of the subfamily 1 elements (PPREs) in the regulatory region of target (NR1) in the nuclear receptor superfamily. The NR1 genes as heterodimers with the auxiliary factor RXR. group also includes retinoic acid receptors (RARs), With the PPAR/RXR heterodimers, either partner can Rev-erb, RAR-related orphan receptors (RORs), bind cognate ligands and elicit ligand-dependent oxysterol receptors (LXRs), vitamin D3 receptors transactivation (Kliewer et al. 1992). The canonical (VDRs), and the nuclear xenobiotic receptor (constitu- PPRE contains two direct repeats of the hormone tive androstane receptor, CAR). PPARs and TRs share a response element (HRE) half site (AGGTCA) with a conserved DNA-binding domain (DBD) and exert their 1 bp spacer in between (DR1; Kliewer et al. 1992, activity partly by heterodimerization with a common Tugwood et al. 1992). partner, the retinoid X receptor (RXR), to regulate the Natural and synthetic ligands have been reported for transcription of target genes. PPARs and TRs each have the three PPAR isotypes (Balakumar et al. 2007, diverse effects on developmental and metabolic pro- Bensinger & Tontonoz 2008; Table 1 and Fig. 2). For cesses as well as in diseases such as obesity, diabetes, and PPARa, ligands include natural unsaturated fatty acids cancer. The first part of this review describes current (FAs), leukotriene, hydroxyeicosatetraenoic acids understanding of PPAR and TR biology. The second (HETEs), and synthetic hypolipemia-inducing drugs part highlights recent advances in the understanding of such as fibrates. The PPARd ligands are less well known, molecular mechanisms underlying the PPAR–TR cross- but FAs have been suggested to be natural ligands for talks, with particular emphasis on the role of such this subtype of PPAR (Fyffe et al. 2006). Recent studies crosstalk in metabolism and carcinogenesis. identified a few more PPARd agonists, namely tetra- decylthioacetic acid (TTA), L-165041, and GW501516 Peroxisome proliferator-activated receptors (Berger et al. 1999, Oliver et al. 2001, Westergaard et al. 2001). For PPARg, endogenous ligands include PPARs, which consist of PPARa (NR1C1), PPARb/d polyunsaturated FAs, prostanoids, and oxidized FAs (NR1C2, hereafter referred to as PPARd), and PPARg found in low-density lipoproteins (Forman et al. 1995, Journal of Molecular Endocrinology (2010) 44, 143–154 DOI: 10.1677/JME-09-0107 0952–5041/10/044–143 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access 144 CLUand S-Y CHENG . Crosstalk of TR with PPAR signalling DBD LBD glucose metabolism and insulin sensitization. That A Domains: A/B CD E/F PPARg also has a dominant role in adipogenesis is B PPAR isoforms: 1 100 174 468 α suggested by many loss-of-function studies both in vivo 1 73 146 441 and in vitro (Fajas et al. 2001). β/δ 86% 70% 1 109 183 477 γ1 83% 68% 1 29 137 211 505 Thyroid hormone receptors γ2 83% 68% α In humans, TRs are encoded by two genes, THRA and C TR isoforms: 1 51 128 410 α1 THRB, located at chromosomes 17 and 3 respectively. 1 154 The THRA gene encodes three TRa (NR1A1) isoforms, ∆α1 1 51 128 370 409 492 TRa1, TRa2, and TRa3, which differ in their carboxyl α2 terminus as a result of alternative splicing of the 1 115 154 237 ∆α2 primary transcripts (Fig. 1). TRa1 binds triiodothy- 1 51 128 370 453 α3 ronine (T3) and activates or represses target genes, whereas TRa2andTRa3donotbindT3,and β D TR isoforms: 1 94 107 174 181 461 β1 may antagonize T3 action (Izumo & Mahdavi 1988, 1 147 160 227 234 514 Mitsuhashi et al. 1988, Macchia et al. 2001). The THRA β2 gene also yields two truncated proteins known as 1 23 36 103 110 390 β3 TRDa1 and TRDa2, which play a role in intestinal 1 8 288 ∆β3 development (Chassande et al. 1997, Plateroti et al. 2001). The THRB gene encodes two amino-terminal Figure 1 Schematic representation of the structures of PPARs TRb (NR1A2) protein variants – TRb1 and TRb2. In and TRs. (A) Modular domain structures of nuclear receptors in general. Two most conserved domains, DBD (C domain) and LBD rodents, the same gene also gives rise to TRb3 and a (E/F domain), are colored in gray and black respectively. (B) The truncated protein TRDb3, which lacks the DBD human PPAR homologs. Compared with the DBD of PPARa (Williams 2000, Harvey et al. 2007). (NR1C1), sequence homology is 86 and 83% in PPARb/d TRs bind to thyroid hormone response elements (NR1C2) and PPARg1/2 (NR1C3) respectively. In LBD, sequences are less conserved with only 70 and 68% of homology (TREs) in target genes as homodimers as well as for PPARb/d and PPARg1/2 respectively using the sequence of heterodimers with RXR. Most naturally occurring PPARa as a reference. (C and D) Structural comparison of rat positive TREs identified to date include two repeats of TRa isoforms (C) and rat TRb isoforms (D). The areas of identical the half site 50-AGGTCA-30, which is also shared by shading indicate conserved sequences among the isoforms. The PPREs arranged as a direct repeat with 4 bps between three major TRa isoforms (TRa1, a2, and a3) mainly differ in LBD at the carboxyl terminus; TRb isoforms (TRb1, b2, and b3) mainly the two half sites (DR4). Among known TREs, inverted differ in amino-terminal A/B domain. repeats (also called palindromes; e.g. GGTCAT- GACCTA) and everted repeats (e.g. GACCT(N6)- AGGTCA, N: any nucleotide) have also been reported Kliewer et al. 1995, Davies et al. 2001). Synthetic ligands (Glass et al. 1988, Brent et al. 1989, Farsetti et al. 1992, g for PPAR include anti-diabetic drugs, such as rosigli- Forman et al. 1992). TRs have also been shown to tazone and pioglitazone of the thiazolidinedione class. heterodimerize with other nuclear receptors, such as This wide variety of ligands for PPARs requires a flexible PPARs and VDRs (Bogazzi et al. 1994, Schrader et al. plasticity in the PPAR ligand-binding domain, which is 1994). In the presence of PPARa,TRb has binding suggested by the PPARg crystallized structure (Nolte affinity to a DR2 present in the myelin proteolipid et al. 1998). protein gene promoter but not to the classical TRE, PPARa is predominantly expressed in tissues with DR4, located in the malic enzyme gene. Upon thyroid high turnover rates of FA metabolism, such as liver, hormone stimulation, the DR2-driven reporter gene is brown adipose tissue (BAT), heart, and kidney. The activated by the TRb–PPARa heterodimer but not by target genes of PPARa are mainly involved in mito- TRa–PPARa,TRa–RXRb,orTRb–RXRb. Three amino chondrial and peroxisomal b-oxidation of FAs and acids in the D box of the DBD in TRb are critical for this apolipoprotein synthesis. PPARd is ubiquitously heterodimerization. The dissimilarity of the D boxes expressed in tissues. Its target genes are involved in between TRb and TRa may be responsible for this FA oxidation, fuel switch, mitochondrial respiration, isoform-dependent protein interaction and the DNA- and thermogenesis (Barish et al. 2006, Furnsinn et al. binding sequence specificity (Bogazzi et al.1994). 2007). PPARg expression is mainly found in BAT and In humans, the DBDs of TRs and PPARs are highly white adipose tissue (WAT) and, to a lesser extent, in homologous. Importantly, TRs and PPARs share the the large intestine, retina, and some immune cells (e.g. same proximal box (P-box) sequence in DBD, which is macrophage and T lymphocyte; Ricote et al. 1998, critical in sequence-specific recognition of HRE by Harris & Phipps 2001). Activation of PPARg affects NRs, while providing contact surface with the major Journal of Molecular Endocrinology (2010) 44, 143–154 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access Crosstalk of TR with PPAR signalling . CLUand S-Y CHENG 145 Table 1 Ligands for peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) Endogenous ligands Synthetic ligands Receptors PPARa Polyunsaturated FAs, leukotriene B4 (LTB4), Clofibrate, fenofibrate, bezafibrate, gemfibrozil, HETE (Kliewer et al. 1997) ciprofibrate, Wy14 643 (Willson et al. 2000), BMS-687453, BMS-711939 (Mukherjee et al. 2008) PPARb/d Unsaturated or saturated long-chain Fas, prostacyclin, TTA, L-165,041, GW501516 eicosanoids, HODE (oxidized FA; Shureiqi et al.