title: Sterol regulatory element-binding proteins are regulators of the rat thyroid peroxidase gene in thyroid cells.
abstract: Sterol regulatory element-binding proteins (SREBPs)-1c and -2, which were initially discovered as master transcriptional regulators of lipid biosynthesis and uptake, were recently identified as novel transcriptional regulators of the sodium-iodide symporter gene in the thyroid, which is essential for thyroid hormone synthesis. Based on this observation that SREBPs play a role for thyroid hormone synthesis, we hypothesized that another gene involved in thyroid hormone synthesis, the thyroid peroxidase (TPO) gene, is also a target of SREBP-1c and -2. Thyroid epithelial cells treated with 25-hydroxycholesterol, which is known to inhibit SREBP activation, had about 50% decreased mRNA levels of TPO. Similarly, the mRNA level of TPO was reduced by about 50% in response to siRNA mediated knockdown of both, SREBP-1 and SREBP-2. Reporter gene assays revealed that overexpression of active SREBP-1c and -2 causes a strong transcriptional activation of the rat TPO gene, which was localized to an approximately 80 bp region in the intron 1 of the rat TPO gene. In vitro- and in vivo-binding of both, SREBP-1c and SREBP-2, to this region in the rat TPO gene could be demonstrated using gel-shift assays and chromatin immunoprecipitation. Mutation analysis of the 80 bp region of rat TPO intron 1 revealed two isolated and two overlapping SREBP-binding elements from which one, the overlapping SRE+609/InvSRE+614, was shown to be functional in reporter gene assays. In connection with recent findings that the rat NIS gene is also a SREBP target gene in the thyroid, the present findings suggest that SREBPs may be possible novel targets for pharmacological modulation of thyroid hormone synthesis.
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Rauer
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Rothe
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.affiliation: Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D019295:Computational Biology; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry; D007438:Introns; D007453:Iodide Peroxidase / Q000378:metabolism*; D009841:Oligonucleotides / Q000737:chemistry; D034622:RNA Interference; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism; D013961:Thyroid Gland / Q000201:enzymology*; D014158:Transcription, Genetic; D000099209:Sodium-Iodide Symporters
chemical_list: D006888:Hydroxycholesterols; D007453:Iodide Peroxidase; D009841:Oligonucleotides; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C497389:Srebf1 protein, rat; C007997:25-hydroxycholesterol