scholarly journals Bcl3 Interacts Cooperatively with Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Coactivator 1α To Coactivate Nuclear Receptors Estrogen-Related Receptor α and PPARα

2009 ◽  
Vol 29 (15) ◽  
pp. 4091-4102 ◽  
Author(s):  
John Yang ◽  
R. Sanders Williams ◽  
Daniel P. Kelly
Keyword(s):  
Energy Metabolism ◽  
Nuclear Receptor ◽  
Transcriptional Profiling ◽  
Gene Promoter ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Responsive Element

ABSTRACT Estrogen-related receptors (ERRs) play critical roles in regulation of cellular energy metabolism in response to inducible coactivators such as peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERRα coactivator. Bcl3 was shown to synergize with PGC-1α to coactivate ERRα. Chromatin immunoprecipitation studies demonstrated that ERRα, PGC-1α, and Bcl3 form a complex on an ERRα-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1α and ERRα, allowing for interaction with both proteins. Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1α, ERRα, and a second nuclear receptor, PPARα. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPARα with PGC-1α in a manner similar to ERRα. We propose that the cooperativity between Bcl3 and PGC-1α may serve as a point of convergence on nuclear receptor targets to direct programs orchestrating inflammatory and energy metabolism responses in heart and other tissues.

scholarly journals Regulation of IGFBP-2 expression during fasting

2015 ◽  
Vol 467 (3) ◽  
pp. 453-460 ◽  
Author(s):  
Hye Suk Kang ◽  
Mi-Young Kim ◽  
Seung-Jae Kim ◽  
Jae-Ho Lee ◽  
Yong-Deuk Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Promoter ◽  
Biological Action ◽  
Peroxisome Proliferator ◽  
Cultured Hepatocytes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akt Phosphorylation ◽  
Primary Cultured Hepatocytes ◽  
Igf Binding ◽  
Responsive Element

Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the most abundant circulating IGFBPs, is known to attenuate the biological action of IGF-1. Although the effect of IGFBP-2 in preventing metabolic disorders is well known, its regulatory mechanism remains unclear. In the present study, we demonstrated the transcriptional regulation of the Igfbp-2 gene by peroxisome-proliferator-activated receptor (PPAR) α in the liver. During fasting, both Igfbp-2 and PPARα expression levels were increased. Wy14643, a selective PPARα agonist, significantly induced Igfbp-2 gene expression in primary cultured hepatocytes. However, Igfbp-2 gene expression in Pparα null mice was not affected by fasting or Wy14643. In addition, through transient transfection and chromatin immunoprecipitation assay in fasted livers, we determined that PPARα bound to the putative PPAR-responsive element between −511 bp and −499 bp on the Igfbp-2 gene promoter, indicating that the Igfbp-2 gene transcription is activated directly by PPARα. To explore the role of PPARα in IGF-1 signalling, we treated primary cultured hepatocytes with Wy14643 and observed a decrease in the number of IGF-1 receptors (IGF-1Rs) and in Akt phosphorylation. No inhibition was observed in the hepatocytes isolated from Pparα null mice. These results suggest that PPARα controls IGF-1 signalling through the up-regulation of hepatic Igfbp-2 transcription during fasting and Wy14643 treatment.

scholarly journals PGC-1α, glucose metabolism and type 2 diabetes mellitus

2016 ◽  
Vol 229 (3) ◽  
pp. R99-R115 ◽  
Author(s):  
Haijiang Wu ◽  
Xinna Deng ◽  
Yonghong Shi ◽  
Ye Su ◽  
Jinying Wei ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Therapeutic Strategies ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cellular Energy ◽  
Cellular Energy Metabolism ◽  
Shed Light

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.

scholarly journals Nuclear Receptor Cofactors in PPARγ-Mediated Adipogenesis and Adipocyte Energy Metabolism

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-11 ◽  
Author(s):  
Emily Powell ◽  
Peter Kuhn ◽  
Wei Xu
Keyword(s):  
Transcriptional Regulation ◽  
Energy Metabolism ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Proper Function ◽  
Peroxisome Proliferator ◽  
Clear Understanding ◽  
Receptor Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Transcriptional Cofactors

Transcriptional cofactors are integral to the proper function and regulation of nuclear receptors. Members of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors are involved in the regulation of lipid and carbohydrate metabolism. They modulate gene transcription in response to a wide variety of ligands, a process that is mediated by transcriptional coactivators and corepressors. The mechanisms by which these cofactors mediate transcriptional regulation of nuclear receptor function are still being elucidated. The rapidly increasing array of cofactors has brought into focus the need for a clear understanding of how these cofactors interact in ligand- and cell-specific manners. This review highlights the differential effects of the assorted cofactors regulating the transcriptional action of PPARγand summarizes the recent advances in understanding the physiological functions of corepressors and coactivators.

scholarly journals Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis

2015 ◽  
Vol 112 (19) ◽  
pp. 6074-6079 ◽  
Author(s):  
Jun Hong Park ◽  
Hong-Jun Kang ◽  
Yun Kyung Lee ◽  
Hyeog Kang ◽  
Jihyun Kim ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Protein Stability ◽  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ssdna Binding ◽  
Cellular Energy ◽  
Mitochondrial Homeostasis ◽  
Ssdna Binding Protein

EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1α expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid β-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.

scholarly journals Hypoxic Exposure Increases Energy Expenditure by Increasing Carbohydrate Oxidation in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yeram Park ◽  
Deunsol Hwang ◽  
Hun-Young Park ◽  
Jisu Kim ◽  
Kiwon Lim
Keyword(s):  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Pyruvate Dehydrogenase ◽  
Hypoxic Condition ◽  
Open Circuit ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hypoxic Exposure ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Aims. Hypoxic exposure improves glucose metabolism. We investigated to validate the hypothesis that carbohydrate (CHO) oxidation could increase in mice exposed to severe hypoxic conditions. Methods. Seven-week-old male ICR mice (n=16) were randomly divided into two groups: the control group (CON) was kept in normoxic condition (fraction of inspired O2=21%) and the hypoxia group (HYP) was exposed to hypoxic condition (fraction of inspired O2=12%, ≈altitude of 4,300 m). The CON group was pair-fed with the HYP group. After 3 weeks of hypoxic exposure, we measured respiratory metabolism (energy expenditure and substrate utilization) at normoxic conditions for 24 hours using an open-circuit calorimetry system. In addition, we investigated changes in carbohydrate mechanism-related protein expression, including hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), and regulator of the genes involved in energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α) in soleus muscle. Results. Energy expenditure (EE) and CHO oxidation over 24 hours were higher in the HYP group by approximately 15% and 34% (p<0.001), respectively. Fat oxidation was approximately 29% lower in the HYP group than the CON group (p<0.01). Body weight gains were significantly lower in the HYP group than in the CON group (CON vs. HYP; 1.9±0.9 vs. −0.3±0.9; p<0.001). Hypoxic exposure for 3 weeks significantly reduced body fat by approximately 42% (p<0.001). PDH and PGC1α protein levels were significantly higher in the HYP group (p<0.05). Additionally, HK2 was approximately 21% higher in the HYP group. Conclusions. Hypoxic exposure might significantly enhance CHO oxidation by increasing the expression of PDH and HK2. This investigation can be useful for patients with impaired glucose metabolism, such as those with type 2 diabetes.

scholarly journals TGFβ1 Controls PPARγExpression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Allan Ramirez ◽  
Erin N. Ballard ◽  
Jesse Roman
Keyword(s):  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Negative Regulator ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Reporter Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
3T3 Fibroblasts ◽  
Nih 3T3

Transforming growth factorβ1 (TGFβ1) promotes fibrosis by, among other mechanisms, activating quiescent fibroblasts into myofibroblasts and increasing the expression of extracellular matrices. Recent work suggests that peroxisome proliferator-activated receptorγ(PPARγ) is a negative regulator of TGFβ1-induced fibrotic events. We, however, hypothesized that antifibrotic pathways mediated by PPARγare influenced by TGFβ1, causing an imbalance towards fibrogenesis. Consistent with this, primary murine primary lung fibroblasts responded to TGFβ1 with a sustained downregulation of PPARγtranscripts. This effect was dampened in lung fibroblasts deficient in Smad3, a transcription factor that mediates many of the effects of TGFβ1. Paradoxically, TGFβ1 stimulated the activation of the PPARγgene promoter and induced the phosphorylation of PPARγin primary lung fibroblasts. The ability of TGFβ1 to modulate the transcriptional activity of PPARγwas then tested in NIH/3T3 fibroblasts containing a PPARγ-responsive luciferase reporter. In these cells, stimulation of TGFβ1 signals with a constitutively active TGFβ1 receptor transgene blunted PPARγ-dependent reporter expression induced by troglitazone, a PPARγactivator. Overexpression of PPARγprevented TGFβ1 repression of troglitazone-induced PPARγ-dependent gene transcription, whereas coexpression of PPARγand Smad3 transgenes recapitulated the TGFβ1 effects. We conclude that modulation of PPARγis controlled by TGFβ1, in part through Smad3 signals, involving regulation of PPARγexpression and transcriptional potential.

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