Article

Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells.

Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Austria.
Endocrinology (Impact Factor: 4.64). 03/2006; 147(2):966-76. DOI: 10.1210/en.2005-0817
Source: PubMed

ABSTRACT A role of uncoupling protein 2 (UCP2) as negative modulator of insulin secretion has been suggested, but the transcriptional pathways regulating beta-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-gamma coactivator-1 alpha (PGC-1alpha). PGC-1alpha potentiates thyroid hormone (T(3))-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 T(3) 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-1alpha 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 beta-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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    • "Besides UCP2 activation by superoxide ions and lipid peroxidation products [11], it has been reported that the levels of UCP proteins in tissues and cells is mainly regulated at the transcriptional level [31] [32]. Here, we show that UCP2 mRNA is induced by GEM, although the identification of the precise mechanisms of this induction needs further investigation. "
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    • "and the opposite expression pattern, suggest that it has a negative influence on UCP2 mRNA expression in vivo. This contrasts with the effect of PPARGC1A on UCP2 gene expression in a rat insulinoma cell line (Oberkofler et al. 2006). However, there is still much debate about the precise function and the tissue-dependent regulation of UCP2 by many genes, and various contradictory results have been reported (Fleury and Sanchis 1999; Villarroya et al. 2007). "
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    • "Various environmental factors modulate Ucp2 transcription: message levels are increased when beta cells are exposed to cold [17], elevated glucose or non-esterified fatty acid levels [15] and hydrogen peroxide [21], whilst it is decreased upon exposure to interleukin-1ß [22]. Most of this information on transcriptional regulation has been obtained from research on rodents, but it is becoming clear that the principal molecular mechanisms are similar in humans, despite a lack of sequence homology within the regulatory region of the respective genes [18]. It is important to realise that UCP2 mRNA and protein levels are not necessarily proportional in beta cells: a low in vivo protein content contrasts for example with a high amount of message, and protein increases may occur without changes in mRNA [23]. "
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