期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 44, 页码 17187-17192出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808207105
关键词
acetyltransferase; caloric restriction; cofactors; deacetylase; SIRT1
资金
- CNRS
- INSERM
- Hopitaux Universitaires de Strasbourg
- EU [QLRT-2001-00930, LSHM-CT-2004-512013]
- NIH [DK59820, HD07857]
- Nestle
Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3(-/-) mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1 alpha. By controlling the expression of the only characterized PGC-1 alpha acetyltransf erase GCN5, SRC-3 induces PGC-1 alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1 alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1 alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1 alpha as an effector to control mitochondrial function and energy homeostasis.
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