Thyroid Hormone Affects the Gene Expression of Retinoid X Receptors in the Adult Rat

Miyata, Hiroshi; Ozawa, Tomonaga; Takeyama, Ken-ichi; Yoshizawa, Yukihiro; Kojima, Ryotaro; Kato, Shigeaki; Masushige, Shoichi

doi:10.1006/bbrc.1993.1308

Cited by 38 publications

(18 citation statements)

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“…RXRα is abundantly expressed in liver and kidney and in less amounts in the intestine. RXRβ is also ubiquitously expressed, but at low levels in liver, kidney and intestine, whereas RXRγ expression is restricted to liver and kidney [36,38,39].…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

Schachtrup

Emmler

Bleck

et al. 2004

Biochemical Journal

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Retinoic acids and long-chain fatty acids are lipophilic agonists of nuclear receptors such as RXRs (retinoic X receptors) and PPARs (peroxisome-proliferator-activated receptors) respectively. These agonists are also ligands of intracellular lipid-binding proteins, which include FABPs (fatty acid-binding proteins). We reported previously that L (liver-type)-FABP targets fatty acids to the nucleus of hepatocytes and affects PPARα activation, which binds together with an RXR subtype to a PPRE (peroxisome-proliferator-responsive element). In the present study, we first determined the optimal combination of murine PPAR/RXR subtypes for binding to known murine FABP-PPREs and to those found by computer search and then tested their in vitro functionality. We show that all PPARs bind to L-FABP-PPRE, PPARα, PPARγ 1 and PPARγ 2 to A (adipocyte-type)-FABP-PPRE. All PPAR/RXR heterodimers transactivate L-FABP-PPRE, best are combinations of PPARα with RXRα or RXRγ . In contrast, PPARα heterodimers do not transactivate A-FABP-PPRE, best combinations are of PPARγ 1 with RXRα and RXRγ , and of PPARγ 2 with all RXR subtypes. We found that the predicted E (epidermal-type)-and H (heart-type)-FABP-PPREs are not activated by any PPAR/RXR combination without or with the PPAR pan-agonist bezafibrate. In the same way, C 2 C 12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells. These results demonstrate that only PPREs of L-and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation.

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Section: Discussionmentioning

confidence: 99%

Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

Schachtrup

Emmler

Bleck

et al. 2004

Biochemical Journal

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“…The PPARs, LXRs, and FXR all form heterodimers with retinoid X receptor (RXR), which facilitates the binding to DNA response elements (28). RXR␣ is the isoform expressed most abundantly in the liver, but RXR␤ and RXR␥ are also present (27,30). In addition to these liposensors, the thyroid hormone receptor (TR) also forms heterodimers with RXR and is well known to regulate the expression of a variety of proteins important in lipid metabolism (1,28,29).…”

Section: In Many Animals Including Humansmentioning

confidence: 99%

Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy

Sweeney

Moser²,

Shigenaga³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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During the third trimester of pregnancy, there is an increase in serum triglyceride and cholesterol levels. The mechanisms accounting for these changes in lipid metabolism during pregnancy are unknown. We hypothesized that, during pregnancy, the expression of nuclear hormone receptors involved in regulating lipid metabolism would decrease. In 19-day pregnant mice, serum triglyceride and non-HDL cholesterol levels were significantly increased, whereas total cholesterol was slightly decreased, because of a decrease in the HDL fraction. Peroxisome proliferator-activated receptor (PPAR)␣, PPAR␤/␦, and PPAR␥, liver X receptor (LXR)␣ and LXR␤, farnesoid X receptor (FXR), and retinoid X receptor (RXR)␣, RXR␤, and RXR␥ mRNA levels were significantly decreased in the livers of 19-day pregnant mice. Additionally, the expressions of thyroid receptor (TR)␣, pregnane X receptor, sterol regulatory element-binding proteins (SREBP)-1a, SREBP-1c, SREBP-2, and liver receptor homolog 1 were also decreased, whereas the expression of TR␤, constitutive androstane receptor, and hepatic nuclear factor 4 showed no significant change. mRNA levels of the PPAR target genes carnitine-palmitoyl transferase 1␣ and acyl-CoA oxidase, the LXR target genes SREBP1c, ATP-binding cassettes G5 and G8, the FXR target gene SHP, and the TR target genes malic enzyme and Spot14 were all significantly decreased. Finally, the expressions of PPAR␥ coactivator (PGC)-1␣ and PGC-1␤, known activators of a number of nuclear hormone receptors, were also significantly decreased. The decreases in expression of RXRs, PPARs, LXRs, FXR, TRs, SREBPs, and PGC-1s could contribute to the alterations in lipid metabolism during late pregnancy. farnesoid X receptor; liver X receptor; peroxisome proliferator-activated receptor; retinoid X receptor; lipid metabolism IN MANY ANIMALS, INCLUDING HUMANS, there is an increase in serum triglyceride and cholesterol levels during the third trimester of pregnancy because of an increase in circulating VLDL and LDL (16,17,46). A number of factors contribute to this increase in circulating lipids (16 -18). Adipose tissue lipoprotein lipase activity is reduced (18), leading to a decrease in the clearance of triglyceride-rich lipoproteins. Moreover, triglyceride synthesis is decreased in adipose tissue, whereas lipolysis is enhanced during pregnancy (18), resulting in an increase in serum free fatty acid levels. In the liver, pregnancy leads to a reduction in fatty acid oxidation (15), although fatty acid synthesis is increased (62). The increase in de novo fatty acid synthesis and the enhanced delivery of fatty acids from adipose tissue coupled with the decrease in fatty acid oxidation increase the pool of fatty acids available in the liver, resulting in an increase in triglyceride synthesis (58). The activity of diacylglycerol acetyltransferase, a key enzyme in the synthesis of triglycerides, is also increased in the liver during pregnancy (50). This increase in triglyceride synthesis in the liver leads to an increase in the hepatic produc...

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“…Because the ligand binding of T $ receptors can either activate or repress the transcription of target genes [18,20,21], we considered the possibility that T $ might decrease the levels of RARs, which are critical for mucin gene expression in NHTBE cells [8]. It has been shown in rats that thyroid hormone up-regulates RXR-β and down-regulates RXR-γ [37,38]. We found that treatment with T $ markedly decreased the levels of RAR-α, RAR-β, RXR-α and RXR-γ proteins in NHTBE cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of mucin gene expression in human tracheobronchial epithelial cells by thyroid hormone

Gray

Nettesheim

Basbaum

et al. 2001

Biochemical Journal

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We reported previously that the expression of the gene encoding MUC5AC mucin in human airway epithelial cells is controlled by retinoic acid via the retinoic acid receptor (RAR)-α and that 3,3′,5-tri-iodothyronine (T3) inhibits the expression of MUC5AC. The purpose of the present study was to identify mechanisms mediating the effect of T3. T3 has been shown to inhibit gene expression via several mechanisms, either by enhancing or repressing the transcription of target genes or by the regulation of post-transcriptional events. Results showed that T3 strongly inhibited MUC5AC-driven luciferase activity in normal human tracheobronchial epithelial cells that had been transiently transfected with a MUC5AC–luciferase reporter construct; however, it did not affect MUC5AC mRNA stability. These results indicate that T3 suppresses MUC5AC expression at the transcriptional level. An analysis of deletion constructs showed that deletion of the region downstream of 3kb resulted in markedly decreased levels of MUC5AC transcription in the absence of T3 (i.e. under control conditions) as well as a loss of responsiveness to the inhibitory effects of T3. This suggests that this region might contain elements important for the activation as well as the repression of MUC5AC transcription. To determine whether T3 modulates retinoic-acid-dependent MUC5AC transcription via an alteration in the abundance of retinoid receptor proteins, we examined the type and abundance of these receptors in nuclear extracts of airway epithelial cells grown in the presence or absence of T3. Western blots showed that T3 markedly decreased several types of retinoid receptor while not affecting T3 receptor proteins. Consistent with this finding were gel-shift assays revealing a decrease in RAR–retinoic acid response element complexes obtained from T3-treated cells. We propose that T3 might inhibit retinoid-dependent MUC5AC expression by decreasing retinoid receptor levels and thereby decreasing the transcriptional activation of this gene for mucins.

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Thyroid Hormone Affects the Gene Expression of Retinoid X Receptors in the Adult Rat

Cited by 38 publications

References 0 publications

Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins

Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy

Regulation of mucin gene expression in human tracheobronchial epithelial cells by thyroid hormone

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