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Regulation of Thyroid Hormone Activation Via the Liver X-Receptor/Retinoid X-Receptor Pathway

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Regulation of Thyroid Hormone Activation Via the Liver X-Receptor/Retinoid X-Receptor Pathway 179 Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway Marcelo A Christoffolete*, Ma´rton Doleschall1,*, Pe´ter Egri1, Zsolt Liposits1, Ann Marie Zavacki2, Antonio C Bianco3 and Bala´zs Gereben1 Human and Natural Sciences Center, Federal University of ABC, Santo Andre-SP 09210-370, Brazil 1Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, Budapest H-1083, Hungary 2Division of Endocrinology, Diabetes, and Hypertension, Thyroid Section, Brigham and Women’s Hospital, Boston, Massachusetts MA 02115, USA 3Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida FL 33136, USA (Correspondence should be addressed to B Gereben; Email: [email protected]) *(M A Christoffolete and M Doleschall contributed equally to this work) (M Doleschall is now at Inflammation Biology and Immungenomics Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary) Abstract Thyroid hormone receptor (TR) and liver X-receptor (LXR) investigated if 9-cis retinoic acid (9-cis RA), the ligand for are the master regulators of lipid metabolism. Remarkably, a the heterodimeric partner of TR and LXR, RXR, could mouse with a targeted deletion of both LXRa and LXRb is regulate the hDIO2 promoter. Notably, 9-cis RA repressed resistant to western diet-induced obesity, and exhibits ectopic the hDIO2 luciferase reporter (1 mM, approximately four- liver expression of the thyroid hormone activating type 2 fold) in a dose-dependent manner, while coexpression of an deiodinase (D2). We hypothesized that LXR/retinoid inactive mutant RXR abolished this effect. However, it is X-receptor (RXR) signaling inhibits hepatic D2 expression, unlikely that RXR homodimers mediate the repression of and studied this using a luciferase reporter containing the hDIO2 since mutagenesis of a DR-1 at K506 bp did not human DIO2 (hDIO2) promoter in HepG2 cells. Given that, interfere with 9-cis RA-mediated repression. Our data in contrast to mammals, the chicken liver normally expresses indicate that hDIO2 transcription is negatively regulated by D2, the chicken DIO2 (cDIO2) promoter was also studied. both 22(R)-OH-cholesterol and 9-cis RA, which is 22(R)-OH-cholesterol negatively regulated hDIO2 in a consistent with LXR/RXR involvement. In vivo,the dose-dependent manner (100 mM, approximately twofold), inhibition of D2-mediated tri-iodothyronine (T3) production while it failed to affect the cDIO2 promoter. Truncations in by cholesterol/9-cis RA could function as a feedback loop, the hDIO2 promoter identified the region K901 to given that T3 decreases hepatic cholesterol levels. K584 bp as critical for negative regulation. We also Journal of Endocrinology (2010) 205, 179–186 Introduction The DIO2 gene encodes type 2 deiodinase (D2), a tightly regulated oxidoreductase selenoenzyme that catalyzes thyroid Thyroid hormone receptor (TR) and liver X-receptors hormone activation by converting thyroxine (T4)toT3, thus (LXRs) are the key regulators of lipid metabolism. Both generating ligand for TR (Gereben et al. 2008). Remarkably, these receptors prefer to bind to a direct repeat of the a mouse with a targeted disruption of LXRa and LXRb consensus DNA-binding site separated by a 4 bp spacing (double LXR knockout (KO) mice) is resistant to western (DR-4), and thus can coordinately regulate gene expression diet-induced obesity, and exhibits ectopic liver expression of through this motif (Wu & Koenig 2000, Kalaany & D2 accompanied by increased expression of T3 target genes Mangelsdorf 2006). LXR can be activated by cholesterol, involved in fatty acid utilization (Kalaany et al. 2005). In this while tri-iodothyronine (T3) binding to TR has profound model, hepatic induction of D2 expression in LXR KO mice effects on the expression profile of thyroid hormone- was dependent on dietary cholesterol, but not on SREBP-1c- dependent genes. Both the receptors can heterodimerize mediated lipogenic pathways. Furthermore, it has been with retinoid X-receptor (RXR), and thus their signaling is demonstrated that bile acids, the principal products of also regulated by 9-cis retinoic acid (9-cis RA; Glass 1994, cholesterol catabolism, prevent obesity in wild-type mice, Willy et al. 1995, Castillo et al. 2004). but not in D2 KO mice, by indirectly increasing D2 Journal of Endocrinology (2010) 205, 179–186 DOI: 10.1677/JOE-09-0448 0022–0795/10/0205–179 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 02:39:51PM via free access 180 M A CHRISTOFFOLETE, M DOLESCHALL and others . D2 regulation via LXR/RXR expression via the G-protein-coupled receptor TGR5 genome with DIO2 being identified on chromosome #5. (GPBAR1; Watanabe et al. 2006). A w5.7kbcDIO2 50 FR fragment was isolated using the The molecular links between cholesterol and D2-catalyzed Expand Long Template PCR System (Roche) with chicken thyroid hormone activation are presently unclear. We genomic DNA as the template, and it was cloned into hypothesized that the LXR/RXR signaling pathways inhibit pGemT vector. A w3.6kbcDIO2 50FR was amplified on hepatic D2 expression in mammals. In order to better this template using the same kit and the following understand the regulation of fat metabolism, we investigated oligonucleotides: sense, TGCACTGTGGATAATCCATC- the effect of the LXR/RXR pathway on D2 expression by CAGGTACCACTCT; antisense, GTTTTAGCTTGC- characterizing the response of human DIO2 (hDIO2) TTCCTTGAAGCCTTTTATACATTC. The resulting promoter to both 22(R)-OH-cholesterol/LXR and 9-cis fragment was cloned between the KpnI and Klenow blunted RA/RXR pathways in human hepatic HepG2 cells. Notably, NheI sites of the pGL3-basic vector, and was confirmed by while D2 is not normally expressed in the mammalian liver sequencing (Promega). (Croteau et al. 1996), it is expressed in the chicken (Gereben et al. 1999). Given this contrast, we also cloned the Promoter studies chicken DIO2 (cDIO2) promoter, and studied its respon- siveness to the LXR/RXR signaling pathways. Our results Promoter studies using a luciferase reporter were performed indicate that the hDIO2 promoter is potently down-regulated as described previously (Fekete et al. 2004, Zeold et al. 2006). at the transcriptional level by both LXR and RXR ligands, As internal controls, hGH and Renilla expression vectors while in contrast, the cDIO2 promoter is unaffected by (phRL-hbactin-213C932) were used (Gereben et al. 2001, 22(R)-OH-cholesterol treatment. Zeold et al. 2006, Doleschall et al. 2007). The CRE was induced with the coexpression of the a-catalytic subunit of protein kinase A (PKA; Maurer 1989) as described (Gereben Materials and Methods et al. 2001). Luciferase activity was determined using the Dual-Luciferase Reporter Assay System (Promega). Where Cell culture and transfection indicated, an empty CDM8 expression vector was used in the HepG2 cells of human hepatoma origin were maintained control transfections. The results are expressed as Luciferase/ under standard conditions in DMEM supplemented with hGH or Luciferase/Renilla ratios. 10% FBS. To remove lipids for experiments with 22(R)- OH-cholesterol (Sigma), serum was double stripped as Statistical analysis described (Larsen et al. 1986). The concentration of 22(R)- G OH-cholesterol and 9-cis RA (Sigma) used in the treatments Results are presented as means S.D. Analysis was statistically is described in the legends, and treatments were performed for preformed using an unpaired t-test, or one-way ANOVA followed by Newman–Keuls post hoc testing when multiple at least 20 h. The vehicles for 22(R)-OH-cholesterol and 9-cis ! . RA were ethanol and DMSO respectively. Transient comparisons were made. P 0 05 was considered statistically transfection was performed using Lipofectamine (Invitrogen) significant. according to the manufacturer’s instructions. Constructs and mutagenesis Results The human RXRa and LXRb expression vectors were described earlier (Seol et al. 1995). The human RXRaD19C Treatment with 22(R)-OH-cholesterol and 9-cis RA nega- mutant lacks the last 19 amino acids (aa 444–462) and the AF- tively regulated the hDIO2 promoter in HepG2 cells 2 region, but retains heterodimerization (Zavacki et al. 1997). transfected with LXRb and RXRa in a dose-dependent The 6.9kb 50 flanking region (FR) hDIO2 luciferase manner with approximately twofold suppression of transcrip- promoter constructs and their truncated forms were described tional activity at a dose of 100 and 1 mM respectively previously (Zeold et al. 2006). PCR-based site-directed (Fig. 1A). Treatment with 22(R)-OH-cholesterol alone in mutagenesis was used to mutate the DR-1 site in the hDIO2 LXRb-transfected HepG2 cells caused a similar effect 50FR. In short, overlapping PCR was used to generate the (Fig. 1B). In contrast, a 3!DR-4 binding site containing mutant cassette that was inserted between the PacI/NheI sites luciferase promoter control construct was induced under of the 6.9kb50 FR hDIO2 luciferase constructs. similar conditions in the presence of only LXRb by approximately threefold, while coexpression of LXRb and RXRa induced the control by approximately fourfold Cloning of the cDIO2 promoter (Fig. 1C). In the control experiments, we also tested the The GenBank no. AF125575 chicken D2 RNA sequence responsiveness of a pGL3-basic construct containing 880 bp (Gereben et al. 1999) was aligned to the chicken genomic of the mouse type 1 deiodinase (D1) promoter to 22(R)- sequence to locate the DIO2 promoter in the chicken OH-cholesterol and no change was observed, further Journal of Endocrinology (2010) 205, 179–186 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 02:39:51PM via free access D2 regulation via LXR/RXR . M A CHRISTOFFOLETE, M DOLESCHALL and others 181 A Human DIO2 B Human DIO2 C 3×DR-4-Luc 10 ng CDM8 10 ng LXRβ β 10 ng CDM8 10 ng LXRβ + 10 ng RXRα 10 ng LXR 40 10 ng LXRβ + 1 ng RXRα 1·50 5 # 1·25 30 4 1·00 ** *** * 20 *** * * * 0·75 *** 3 * * 0·50 2 RLU/GH a.u.
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