共查询到20条相似文献,搜索用时 15 毫秒
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Auld KL Berasi SP Liu Y Cain M Zhang Y Huard C Fukayama S Zhang J Choe S Zhong W Bhat BM Bhat RA Brown EL Martinez RV 《Journal of molecular endocrinology》2012,48(2):177-191
Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor α (ERRα (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRα modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRα modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRα showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1α, PGC-1α) stimulatory effects. Interestingly, knockdown of ERRα expression also enhanced WNT signaling. In combination, these data indicated that ERRα could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1α. The observed Wnt pathway modulation was cell intrinsic and did not alter β-catenin nuclear translocation but was dependent on DNA binding of ERRα. We also found that expression of active ERRα correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRα in modulating the Wnt pathway. In conclusion, this work identifies ERRα, in conjunction with co-activators such as PGC-1α, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting β-catenin nuclear translocation. 相似文献
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Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand 下载免费PDF全文
Willy PJ Murray IR Qian J Busch BB Stevens WC Martin R Mohan R Zhou S Ordentlich P Wei P Sapp DW Horlick RA Heyman RA Schulman IG 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(24):8912-8917
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Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) and mitochondrial function by MEF2 and HDAC5 总被引:6,自引:0,他引:6 下载免费PDF全文
Czubryt MP McAnally J Fishman GI Olson EN 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(4):1711-1716
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PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity 总被引:2,自引:0,他引:2 下载免费PDF全文
Kamei Y Ohizumi H Fujitani Y Nemoto T Tanaka T Takahashi N Kawada T Miyoshi M Ezaki O Kakizuka A 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(21):12378-12383
A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPARgamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1beta/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial beta-oxidation in skeletal muscle. As a result, the PGC-1beta/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1beta/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs. 相似文献
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Hu X Xu X Lu Z Zhang P Fassett J Zhang Y Xin Y Hall JL Viollet B Bache RJ Huang Y Chen Y 《Hypertension》2011,58(4):696-703
The normal expression of myocardial mitochondrial enzymes is essential to maintain the cardiac energy reserve and facilitate responses to stress, but the molecular mechanisms to maintain myocardial mitochondrial enzyme expression have been elusive. Here we report that congestive heart failure is associated with a significant decrease of myocardial estrogen-related receptor-α (ERRα), but not peroxisome proliferator-activated receptor-γ coactivator 1α, in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRα expression that was significantly correlated to the degree of left ventricular dysfunction, pulmonary congestion, and decreases of a group of myocardial energy metabolism-related genes. We found that the metabolic sensor AMP activated protein kinase (AMPK) regulates ERRα expression in vivo and in vitro. AMPKα2 knockout decreased myocardial ERRα (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptor-γ coactivator 1α expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKα significantly induced ERRα mRNA, protein, and promoter activity. Conversely, selective gene silencing of AMPKα2 repressed ERRα and its target gene levels, indicating that AMPKα2 is involved in the regulation of ERRα expression. In addition, overexpression of ERRα in AMPKα2 knockout neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism-related genes. These data support an important role for AMPKα2 in regulating the expression of myocardial ERRα and its downstream mitochondrial enzymes. 相似文献
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