Unliganded thyroid hormone receptor-beta1 represses liver X receptor alpha/oxysterol-dependent transactivation.
The thyroid hormone receptor (TR) and liver X receptor (LXR)-alpha are members of the nuclear hormone receptor family and are ligand-dependent transcription factors. Among the promoter target genes, TR and LXR recognize the T3 response element and LXR response element (LXRE), respectively. Because T3 response elements and LXREs have similar configurations, referred to as direct repeat 4, we investigated the possibility of cross-talk between the two ligand-dependent signal transduction pathways. We found that TRbeta1, a major isoform of TR in the liver, binds and transactivates LXREs derived from the mouse mammary tumor virus long-terminal repeat and the promoter of the sterol regulatory element binding protein 1c. Moreover, unliganded TRbeta1 suppresses promoter activity driven by LXRalpha and its ligand, whereas transactivation by T3-bound TRbeta1 is not affected by LXRalpha in the presence or absence of oxysterols. Gel shift, mammalian two-hybrid, and glutathione S-transferase pull-down assays demonstrated the direct binding of TRbeta1 to these LXREs and revealed that the interaction between TRbeta1 and corepressors is important to the unliganded TR-mediated suppression of LXRalpha-transactivation. Our findings suggest that T3 and TR influence lipid metabolism regulated by oxysterol/LXRalpha at the transcriptional level.
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Kotaro
K
Kawai
Shigekazu
S
Sasaki
Hiroshi
H
Morita
Takeshi
T
Ito
Sadako
S
Suzuki
Hiroko
H
Misawa
Hirotoshi
H
Nakamura
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D019281:Dimerization; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D008024:Ligands; D050356:Lipid Metabolism; D008113:Liver Neoplasms; D000071518:Liver X Receptors; D016296:Mutagenesis; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014284:Triiodothyronine / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine