Feature Review
Steroid receptor coactivators: servants and masters for control of systems metabolism

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Highlights

  • SRCs are required for diverse metabolic processes.

  • SRCs impact metabolic systems physiology.

  • SRC dysfunction confers metabolic pathophysiology.

  • SRCs bridge anabolic and catabolic functions for the maintenance of energy homeostasis.

Coregulator recruitment to nuclear receptors (NRs) and other transcription factors is essential for proper metabolic gene regulation, with coactivators enhancing and corepressors attenuating gene transcription. The steroid receptor coactivator (SRC) family is composed of three homologous members (SRC-1, SRC-2, and SRC-3), which are uniquely important for mediating steroid hormone and mitogenic actions. An accumulating body of work highlights the diverse array of metabolic functions regulated by the SRCs, including systemic metabolite homeostasis, inflammation, and energy regulation. We discuss here the cooperative and unique functions among the SRCs to provide a comprehensive atlas of systemic SRC metabolic regulation. Deciphering the fractional and synergistic contributions of the SRCs to metabolic homeostasis is crucial to understanding fully the networks underlying metabolic transcriptional regulation.

Section snippets

The fundamentals of SRCs

With over 450 coregulators identified to date, the SRCs (see Glossary) offer tremendous flexibility in transcriptional regulation and gene expression (Box 1). The three family members, SRC-1 (NCOA1), SRC-2 (NCOA2/Grip1/Tif2), and SRC-3 (NCOA3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) belong to the structurally homologous p160 family of coactivators. The most conserved domain is the N-terminal basic helix-loop-helix-Per/ARNT/Sim (b-HLH-PAS) that facilitates protein–protein interactions with other

WAT and BAT

SRC regulation of lipid metabolism is complex and largely deduced using congenic mouse knockout models. Each of the SRCs displays unique roles in lipid metabolism including fatty acid biosynthesis, catabolism, and adipogenesis. Overall, the SRC-1−/− (Ncoa1−/−) mouse exhibits decreased energy expenditure resulting in increased adiposity, and both SRC-2−/− and SRC-3−/− mice are lean and resistant to obesity upon challenge with a high-fat diet (HFD) 12, 13. Interestingly, a HFD alters the ratio of

Carbohydrate metabolism

The SRCs function in various elements of carbohydrate metabolism including glycolysis/gluconeogenesis, the tricarboxylic acid (TCA) cycle, and the insulin response. Analysis of gene expression from hepatic microarrays following ablation of each SRC family member revealed clear metabolic roles for SRC-1 and SRC-2 in carbohydrate metabolism [25]. More specifically, pathway analysis of genes influenced by the loss of the SRCs revealed that SRC-1 ablation repressed gene expression for processes

Amino acid metabolism

Amino acid metabolism is fundamental to protein translation and transcription, and all three SRCs impact amino acid homeostasis. Amino acids are key precursors for gluconeogenesis, neurotransmitter biosynthesis, and anaplerotic metabolism. SRC-1, a regulator of gluconeogenesis, also regulates amino acid metabolism in the liver through maintenance of tyrosine aminotransferase (TAT) gene expression which, in turn, alters tyrosine levels. Hepatic SRC-1 ablation also increases other amino acid

Xenobiotic metabolism

The SRCs also play roles in drug and xenobiotic metabolism in the liver. These processes are largely regulated by NR-mediated transcription of genes encoding the cytochrome P450 (CYP) class of enzymes [37]. SRC-1 coactivates several NRs involved in CYP regulation including liver receptor homolog-1 (LRH-1), constitutive androstane receptor (CAR), steroid and xenobiotic receptor (SXR), and hepatocyte nuclear factor 4α (HNF4α). As one specific example, SRC-1 coactivates LRH-1 on the Cyp7a1

Steroid metabolism

The SRCs are important mediators of steroid metabolism. SRC-1 regulation of the hypothalamic–pituitary–adrenal (HPA) axis is well characterized [45]. SRC-1−/− mice are glucocorticoid-resistant and fail to increase glucocorticoid receptor (GR) target gene expression after dexamethasone treatment. Chronic stress increases corticosterone levels in SRC-1−/− mice, but their glucocorticoid-induced stress response is blunted [45]. When overexpressed, SRC-1 splice variants differentially act as

Concluding remarks and future perspectives

This review highlights the overarching involvement of SRCs in lipid, carbohydrate, amino acid, xenobiotic, and steroid metabolism (Figure 2, Figure 3). The SRCs serve as metabolic sensors and coordinators across tissues regulating inputs for diverse processes including, but not limited to, feeding/sleeping behavior, stress response, and reproduction, demonstrating that each SRC family member is a conserved master regulator in systems physiology. Coordination of SRC activity within or between

Acknowledgements

Support was provided by the NIH through F31 CA171350 to E.S. Additionally, this work was supported by PO1 DK059820, RO1 HD007857 and RO1 HD008188 to B.W.O.

Glossary

Adaptive thermogenesis
a metabolic response activated in BAT in response to cold exposure that results in uncoupling of mitochondrial respiration for the production of ATP, allowing for energy to be dissipated as heat.
Brown adipose tissue (BAT)
a mitochondria-rich form of adipose that is responsible for uncoupling mitochondrial respiration for heat generation.
High-fat diet (HFD)
a diet with a disproportional percentage (i.e., 45–60%) of calories from fat. HFD is used to generate diet-induced

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