SIRT1 is involved in glucocorticoid-mediated control of uncoupling protein-3 gene transcription.
UCP3 (uncoupling protein-3) is a mitochondrial membrane transporter expressed preferentially in skeletal muscle. UCP3 lowers mitochondrial membrane potential and protects muscle cells against an overload of fatty acids, and it probably reduces excessive production of reactive oxygen species. Accordingly, ucp3 gene transcription is highly sensitive to fatty acid-dependent stimulation and also to other unrelated stress signals. In this study, glucocorticoids are identified as major inducers of ucp3 gene transcription in muscle. Glucocorticoids activate the transcription of the ucp3 gene through a glucocorticoid receptor-binding site in the promoter region. Glucocorticoids are capable of inducing ucp3 gene transcription independently from the myogenic regulatory factor MyoD, in contrast with the transcriptional activation of the ucp3 gene through other nuclear hormone receptors. An interplay of regulatory factors modulates positively (p300) or negatively (histone deacetylases) the action of glucocorticoids on ucp3 gene transcription via histone acetylation or deacetylation processes, respectively. Among them, SIRT1 acts as a major repressor of ucp3 gene expression in response to glucocorticoids. The action of SIRT1 requires its deacetylase activity and results in histone deacetylation in the ucp3 promoter. Moreover, it involves a specific impairment of association of p300 with the glucocorticoid receptor. Agents activating SIRT1, such as resveratrol, repress ucp3 gene expression. The control of SIRT1 activity via the metabolic redox status of the cell points to a novel regulatory pathway of ucp3 gene transcription in response to metabolic and stress signaling in muscle cells.
Amat
Ramon
R
Departament de Bioquimica i Biologia Molecular and Institut de Biomedicina, Universitat de Barcelona and CIBER Fisiopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III, Avda Diagonal 645, 08028-Barcelona, Spain.
Solanes
Gemma
G
Giralt
Marta
M
Villarroya
Francesc
F
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D007473:Ion Channels / Q000096:biosynthesis*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D000071247:Uncoupling Protein 3; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005227:Fatty Acids; D005938:Glucocorticoids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D013267:Stilbenes; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D050880:p300-CBP Transcription Factors; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol