The Uncoupling Protein-3 Gene Is Transcribed from Tissue-specific Promoters in Humans but Not in Rodents

Esterbauer, Harald; Oberkofler, Hannes; Krempler, Franz; Strosberg, A. Donny; Patsch, Wolfgang

doi:10.1074/jbc.m005713200

Cited by 25 publications

(19 citation statements)

References 52 publications

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“…Thus expression of UCP3 mRNA was higher in human than in rat heart [16,32]. In contrast to rodent brown adipose tissue, where high levels have been reported, little or no expression of UCP3 was detected in human brown adipose tissue [32,33]. Moreover, our data with the 16 kb construct are in agreement with the in vivo distribution of human UCP3 in mice with an 80 kb transgene encompassing 50 kb of 5′ flanking region and containing all the intronic regions [22].…”

Section: Discussionsupporting

confidence: 80%

“…The sizes of the promoter region are shown according to the transcriptional start site determined by Acin et al [19] Each construct contained 657 bp of exon 1 because several transcriptional start sites have been reported [18,19,33] I 8 2 II 3 0 III 3 0 I1 3 2 I2 3 0 I3 3 0 I4 3 2 The constructs contain 3.2 kb of the promoter region, 657 bp of exon 1, the CAT gene and various intronic regions…”

Section: Resultsmentioning

confidence: 99%

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Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

et al. 2009

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Aims/hypothesis Uncoupling protein (UCP) 3 is an inner mitochondrial membrane transporter mainly produced in skeletal muscle in humans. UCP3 plays a role in fatty acid metabolism and energy homeostasis and modulates insulin sensitivity. In humans, UCP3 content is higher in fasttwitch glycolytic muscle than in slow-twitch oxidative muscle and is dysregulated in type 2 diabetes. Here, we studied the molecular mechanisms determining human UCP3 levels in skeletal muscle and their regulation by fasting in transgenic mice. Methods We produced a series of transgenic lines with constructs bearing different putative regulatory regions of the human UCP3 gene, including promoter and intron sequences. UCP3 mRNA and reporter gene expression and activity were measured in different skeletal muscles and tissues. Results The profile of expression and the response to fasting and thyroid hormone of human UCP3 mRNA in transgenic mice with 16 kb of the human UCP3 gene were similar to that of the endogenous human gene. Various parts of the UCP3 promoter did not confer expression in transgenic lines. Inclusion of intron 1 resulted in an expression profile in skeletal muscle that was identical to that of human UCP3 mRNA. Further dissection of intron 1 revealed that distinct regions were involved in skeletal muscle expression, distribution among fibre types and response to fasting. Conclusions/interpretation The control of human UCP3 transcription in skeletal muscle is not solely conferred by the promoter, but depends on several cis-acting elements in intron 1, suggesting a complex interplay between the promoter and intronic sequences.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

et al. 2009

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“…Indeed, inspection of the literature reveals marked differences in the expression of UCP3 between rodents and humans in response to identical physiological conditions ( Table 1). Assuming that these diverse conditions result in similar cellular environments when imposed on both rodents and humans, the resulting differences in UCP3 gene expression might be explained by the reported divergence in the human and rodent promoter regions upstream of the UCP3 gene (15), which could lead to different transcriptional activation among species. However, we also speculate that the two-to threefold lower density of UCP3 in the inner mitochondrial membrane of human muscle (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic

Adhihetty²,

Hood³

2004

Journal of Applied Physiology

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Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis. J Appl Physiol 97: 976 -983, 2004. First published May 14, 2004 10.1152/japplphysiol.00336.2004In an effort to better characterize uncoupling protein-3 (UCP3) function in skeletal muscle, we assessed basal UCP3 protein content in rat intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial subfractions in conjunction with measurements of state 4 respiration. UCP3 content was 1.3-fold (P Ͻ 0.05) greater in IMF compared with SS mitochondria. State 4 respiration was 2.6-fold greater (P Ͻ 0.05) in the IMF subfraction than in SS mitochondria. GDP attenuated state 4 respiration by ϳ40% (P Ͻ 0.05) in both subfractions. The UCP3 activator oleic acid (OA) significantly increased state 4 respiration in IMF mitochondria only. We used chronic electrical stimulation (3 h/day for 7 days) to investigate the relationship between changes in UCP3 protein expression and alterations in state 4 respiration during contractile activity-induced mitochondrial biogenesis. UCP3 content was increased by 1.9-and 2.3-fold in IMF and SS mitochondria, respectively, which exceeded the concurrent 40% (P Ͻ 0.05) increase in cytochrome-c oxidase activity. Chronic contractile activity increased state 4 respiration by 1.4-fold (P Ͻ 0.05) in IMF mitochondria, but no effect was observed in the SS subfraction. The uncoupling function of UCP3 accounted for 50 -57% of the OA-induced increase in state 4 respiration in IMF mitochondria, which was independent of the induced twofold difference in UCP3 content due to chronic contractile activity. Thus modifications in UCP3 function are more important than changes in UCP3 expression in modifying state 4 respiration. This effect is evident in IMF but not SS mitochondria. We conclude that UCP3 at physiological concentrations accounts for a significant portion of state 4 respiration in both IMF and SS mitochondria, with the contribution being greater in the IMF subfraction. In addition, the contradiction between human and rat training studies with respect to UCP3 protein expression may partly be explained by the greater than twofold difference in mitochondrial UCP3 content between rat and human skeletal muscle. skeletal muscle; exercise; mitochondria; uncoupling protein-3

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“…In adult rodents, the UCP2 protein was detected in white adipose tissue, spleen, lung, and stomach (8,17,18), and it was implicated in the regulation of reactive oxygen species production (19,20). UCP3 is present only in skeletal muscle, heart, and brown fat (21)(22)(23)(24)(25). It is linked specifically to lipid metabolism (26 -31), and indirect evidence suggests that this protein contributes to the control of energy expenditure in humans [for refs.…”

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confidence: 99%

Induction of Uncoupling Protein 3 Gene Expression in Skeletal Muscle of Preterm Newborns

et al. 2003

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Prematurity is associated with delayed postnatal activation of mitochondrial oxidative phosphorylation and impaired switch from glycolytic to oxidative metabolism. Fatty acids (FA), which represent a major energy substrate in mature muscle cells, are engaged in the postnatal activation of genes of energy metabolism and lipid oxidation. To understand the mechanism activating mitochondria in human newborns, expression of the genes for mitochondrial uncoupling proteins (UCP) was characterized in autopsy samples of skeletal (n ϭ 28) and cardiac (n ϭ 13) muscles of preterm neonates, who mostly died during the first postnatal month, and two aborted fetuses. Transcripts levels for UCP2, UCP3, and also for genes engaged in the transport of FA between cytoplasm and mitochondria were measured using realtime reverse transcriptase PCR. In accordance with studies in mice, our results document postnatal induction of UCP3 gene expression in skeletal muscle, involvement of nutritional FA in the induction, and a role of UCP3 in mitochondrial FA oxidation. They suggest impaired postnatal activation of UCP3 gene in neonates delivered before approximately 26 wk of gestation. Mean levels of the UCP3 transcript in skeletal muscle were by two orders of magnitude higher than in the heart. In contrast to UCP3, the UCP2 gene was active in fetuses, and its expression was not affected by nutrition. Postnatal switch of glycolytic to oxidative metabolism is of crucial importance for all mammalian neonates. Several studies (1-3) demonstrate the recruitment of energy conversion and ATP synthesis in mitochondria during the early postnatal period as well as insufficient maturation of this mechanism in premature newborns (4, 5). The recruitment of mitochondrial oxidative phosphorylation in the tissues of the newborns reflects changes in the hormonal status and also a shift from glucose to lipids as the major energy source during the early postnatal period (6). However, nutritional FA serve not only as the source of energy but also as modifiers of the gene expression in many tissues (7). The effects of FA on gene expression in the newborns are of great significance with respect to the postnatal maturation of energy metabolism and mitochondrial functions. To understand the mechanisms underlying the adaptation of premature newborns to the extrauterine life, genes engaged in the control of energy metabolism must be identified. The role of the developmental status of the organism and of other possible external factors, such as nutrition, on the expression of the genes must be clarified.UCP represent an important example of developmentally regulated genes participating in the control of mitochondrial energy conversion. They belong to a family of mitochondrial inner membrane transporters and are implicated in the regulation of the proton leak across the membrane. Thus, all UCP may lower the efficiency of mitochondrial ATP production; ABSTRACT691

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The Uncoupling Protein-3 Gene Is Transcribed from Tissue-specific Promoters in Humans but Not in Rodents

Cited by 25 publications

References 52 publications

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Induction of Uncoupling Protein 3 Gene Expression in Skeletal Muscle of Preterm Newborns

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