Coste Agnès, Louet Jean-Francois, Lagouge Marie, Lerin Carles, Antal Maria Cristina, Meziane Hamid, Schoonjans Kristina, Puigserver Pere, O'Malley Bert W, Auwerx Johan
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France.
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17187-92. doi: 10.1073/pnas.0808207105. Epub 2008 Oct 28.
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-1alpha. By controlling the expression of the only characterized PGC-1alpha acetyltransferase GCN5, SRC-3 induces PGC-1alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1alpha as an effector to control mitochondrial function and energy homeostasis.
代谢回路的转录调控需要特定转录因子与共调节因子之间的协调，并且在代谢疾病中常常失调。我们在此描述了共激活因子SRC-3控制能量稳态的机制。与野生型同窝小鼠相比，SRC-3基因敲除小鼠呈现出更有利的代谢状况。SRC-3(-/-)小鼠的这种代谢改善是由于PGC-1α激活导致线粒体功能和能量消耗增加所致。通过控制唯一已被鉴定的PGC-1α乙酰转移酶GCN5的表达，SRC-3诱导PGC-1α乙酰化，从而抑制其活性。有趣的是，热量过剩会诱导SRC-3表达，导致PGC-1α活性和能量消耗受到抑制，而热量限制则会降低SRC-3水平，从而增强PGC-1α活性和能量消耗。总体而言，这些数据表明SRC-3是一个辅助因子网络中的关键环节，该网络利用PGC-1α作为效应器来控制线粒体功能和能量稳态。
