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Role of Peroxisome Proliferator-Activated Receptor- Coactivator-1 in the Transcriptional Regulation of the Human Uncoupling Protein 2 Gene in INS-1E Cells

Department of Laboratory Medicine (H.O., K.K., T.K.F., W.P.), Landeskliniken and Paracelsus Private Medical University Salzburg, A-5020 Salzburg, Austria; and the Department of Internal Medicine (F.K.), Krankenhaus Hallein, A-5400 Hallein, Austria

Address all correspondence and requests for reprints to: Hannes Oberkofler, Ph.D., Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria. E-mail: h.oberkofler{at}salk.at.

A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating ß-cell UCP2 gene expression have been established in rodents only. We show here that the underlying sequence motifs are not conserved in the human gene and provide evidence for regulatory mechanisms involving the transcriptional cofactor peroxisome proliferator-activated receptor- coactivator-1 (PGC-1). PGC-1 potentiates thyroid hormone (T₃)-mediated transcriptional activation of the human UCP2 gene in INS-1E cells. Two thyroid hormone response elements (TREs) located at –322/–317 (TRE1) and –170/–165 (TRE2) were identified, and mutation of either TRE1 or TRE2 abrogated the stimulatory effect of T₃ treatment. Furthermore, two E-box motifs at –911/–906 (E1) and –743/–738 (E2) are involved in the regulation of UCP2 gene expression by sterol regulatory element binding protein isoforms (SREBP)-1a, -1c, and -2. Mutational analysis revealed that the presence of either E1 or E2 is sufficient to mediate activation of UCP2 gene transcription by nuclear active SREBPs. PGC-1 coactivates liver X receptor-mediated expression of SREBP-1c as well as dexamethasone-stimulated SREBP-2 expression in INS-1E cells. These transcriptional responses are antagonized by orphan nuclear receptor short heterodimer partner overexpression, which might explain its positive effects on glucose-stimulated insulin secretion in ß-cells overexpressing UCP2. We also provide evidence that despite a lack of sequence homology within the regulatory region, the principal mechanisms regulating UCP2 gene expression are similar in rats and humans, being consistent with a role for UCP2 as a modulator of insulin secretion in humans.

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