Trends in Endocrinology & Metabolism
Feature ReviewSteroid receptor coactivators: servants and masters for control of systems metabolism
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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ESR1 activating mutations: From structure to clinical application
2023, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Beyond posttranslational modifications, ER can interact with a variety of coactivators and corepressors [17]. Upon translocating to the nucleus, coactivators such as NCOA1, NCOA2, NCOA3, or corepressors like NCOR1, can interact with ER to influence the ability of the nuclear receptor to transcribe a gene [17]. ER also has a number of isoforms that may impact activity.
The NCOA1-CBP-NF-κB transcriptional complex induces inflammation response and triggers endotoxin-induced myocardial dysfunction
2022, Experimental Cell ResearchCitation Excerpt :The activation of TLR4/NF-κB has been observed in multiple inflammation diseases [5–7,13]; however, the underlying mechanism by which NF-κB assembles into a transcriptional complex with other coregulators to induce the expression of proinflammatory cytokine genes is still unknown in EMID pathogenesis. One coactivator with potential involvement in transcriptional complex formation is nuclear receptor coactivator 1 (NCOA1), also known as steroid receptor coactivator 1 (SRC1) [14,15]. NCOA1 overexpression is observed in multiple biological processes, such as tumorigenesis, endocrinology, metabolism, and development [14,15].
Mechanisms of Histone Modifications
2022, Handbook of Epigenetics: The New Molecular and Medical Genetics, Third EditionAn acetylation-enhanced interaction between transcription factor Sox2 and the steroid receptor coactivators facilitates Sox2 transcriptional activity and function
2021, Journal of Biological ChemistryCitation Excerpt :Thus, it is of great interest to determine in the future the structural basis for this acetylation-enhanced interaction between Sox2 and SRC-3, as this may reveal novel acetylation recognition motifs in the SRC family coactivators. As these family coactivators have broad roles in transcriptional regulation and other biological processes (24, 42), our finding they function as readers of acetylated proteins may have roles extending beyond transcriptional regulation by Sox2. HeLa S3 and HEK293T cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (GIBCO, Thermo Fisher) with 10% fetal bovine serum (GIBCO), and CGR8 cells were cultured in Glasgow's minimum essential medium (GIBCO) with 15% fetal bovine serum (GIBCO), 1000 U/ml LIF, 2 mM GlutaMAX, and 0.1 mM β-mercaptoethanol at 37 °C in air atmosphere with 5% CO2.