The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α

Abstract

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␣. By controlling the expression of the only characterized PGC-1␣ acetyltransferase GCN5, SRC-3 induces PGC-1␣ acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1␣ activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1␣ activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1␣ as an effector to control mitochondrial function and energy homeostasis.acetyltransferase ͉ caloric restriction ͉ cofactors ͉ deacetylase ͉ SIRT1

Transcriptional control of brown adipocyte development and physiological function—of mice and men

“…Interestingly, SRC-3 induces GCN5, the major acetyltransferase of PGC-1a (Lerin et al 2006), to repress the transcriptional activity of PGC-1a. Ablation of SRC-3 reduces acetylation of PGC-1a, leading to an increase in mitochondrial biogenesis (Louet et al 2006;Coste et al 2008).…”

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

“…Besides, the SRC family functions as coactivators not only for NR but also for multiple other transcriptional factors (TF), such as nuclear factor kappa B, E2F1 and IGF-1-dependent TFs (York et al, 2010;Ma et al, 2011;Walsh et al, 2012). By coactivating NR and these NFs, all members of the SRC family can modulate diverse genes expression programs and play important roles in growth, metabolism, reproduction and turmorigenesis (Wu et al, 2007;Coste et al, 2008;Yi et al, 2008;Cai et al, 2010).…”

Transcriptional co-factors and hepatic energy metabolism

“…According to microarray analysis of gene expression in the liver by Jeong et al (2006), the ablation of SRC-3 (NCoA3, p300/CBP-interacting protein (p/CIP), thyroid hormone receptor activator molecule 1 (TRAM1)) did not affect liver specific gene regulation but showed a more preferable metabolic profile due to an increase in mitochondria function and energy expenditure via activation of PGC1-alpha [115,123]. It has been shown by NikolaidouNeokosmidou et al (2006) that SRC-3 activated the hepatocyte nuclear factor 4 (HNF4) and thereby the transcription of the HNF4 target gene apolipoprotein C3 (APOC3), which was involved in the binding of apolipoprotein E-containing lipoproteins to cell receptors and their subsequent catabolism [120].…”