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by the direct transcriptional activation of target genes and the indirect downstream effects of the gene products, but also by modulation of other transcription factors. The glucocorticoid receptor was the first receptor to be identified, followed quickly by the estrogen receptor.65 115 1 81 188 Due to its essential role in glucose metabolism, the glucocorticoid receptor will be discussed as an example of this class.

The glucocorticoid receptor (GR) regulates enzymes involved in glucose metabolism and protects from glucose deficiency during the fasted state. Activation of GR by glucocorticoids, such as cortisol, results in a myriad of responses in many different tissues all geared toward ensuring that the plasma glucose levels remain sufficient to support brain function. Glucose is spared in the peripheral tissues, which preferentially use alternative energy sources such as amino acids and triglycerides (TGs). Increased protein degradation and lipolysis in peripheral tissues lead to increased release of gluconeogenic substrates, such as glycerol and amino acids, from these tissues. These gluconeogenic substrates are then taken up by the liver, in which the rate of gluconeogensis and glycogen storage are increased in response to GR activation.

In the basal inactive state, GR resides in the cytosol bound to heat shock pro-teins.77 Ligand binding induces a conformational change that causes the receptor to disassociate from the heat shock proteins and form a homodimer. This conforma-tional change also exposes a nuclear localization signal in the ligand binding domain, facilitating the transport of the homodimer into the nucleus, where it binds to glucocorticoid response elements (GRE) in GR target gene promoters. Once in the nucleus, GR can bind DNA and mediate the transcription of its target genes, such as the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK).77

The anti-inflammatory effects of glucocorticoids, which have proven to be therapeuti-cally valuable, are also mediated by GR. In addition to directly inducing transcription of anti-inflammatory genes, such as lipocortin-1 and secretory leukocyte protease inhibitor (SLPI), GR also inhibits pro-inflammatory transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1).12 This so-called transrepression by GR does not involve its DNA binding or dimerization, as mutant receptors deficient in these functions retain their transrepression abilities.140 Although GR is a much stronger inmmunosuppressor compared to other receptors, it is not a drug candidate for metabolic diseases due to adverse effects, such as induction of hepatic gluconeogenesis.

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