The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α
The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α
复制标题
DOI：
10.1073/pnas.0808207105
复制
发表时间：
2008-11-04
影响因子：
11.1
通讯作者：
Auwerx, Johan
中科院分区：
文献类型：
--
作者：
Coste, Agnes;Louet, Jean-Francois;Auwerx, Johan
代谢回路的转录控制需要特定转录因子和辅调节因子之间的协调，并且通常在代谢疾病中失调。我们在这里的特点的机制，通过共激活SRC-3控制能量稳态。SRC-3基因敲除小鼠相对于其野生型同窝出生小鼠呈现更有利的代谢特征。SRC-3（-/-）小鼠的这种代谢改善是由PGC-1 α激活导致的线粒体功能和能量消耗增加引起的。通过控制唯一表征的PGC-1 α乙酰转移酶GCN 5的表达，SRC-3诱导PGC-1 α乙酰化并因此抑制其活性。有趣的是，SRC-3表达由热量过量诱导，导致PGC-1 α活性和能量消耗的抑制，而热量限制降低SRC-3水平，导致PGC-1 α活性和能量消耗增强。总的来说，这些数据表明SRC-3是辅因子网络中的关键环节，该辅因子网络使用PGC-1 α作为效应子来控制线粒体功能和能量稳态。
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.