Role In Glucocorticoid Action Research Articles

The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome

Glucocorticoids are stress hormones that modulate a large number of physiological actions involved in metabolic, inflammatory, cardiovascular and behavioral processes. The molecular mechanisms and the physiological effects of glucocorticoids have been extensively studied. However, the involvement of glucocorticoid action in the etiology of the Metabolic Syndrome has not been well appreciated. Recently, accumulating clinical evidence and animal genetics studies have attracted growing interest in the role of glucocorticoid action in obesity and insulin resistance. This review will discuss the metabolic effects in the context of glucocorticoid metabolism and establish the association of glucocorticoid action with the features of the Metabolic Syndrome, especially obesity and insulin resistance. Special discussions will be focused on corticosteroid-binding globulin and 11β-hydroxysteroid dehydrogenase type 1, two proteins that mediate glucocorticoid action and have been implicated in the Metabolic Syndrome. Due to the complexities of the glucocorticoid biology and the Metabolic Syndrome and limited space, this review is only intended to provide a general link between the two areas with broad rather than in-depth discussions of clinical, pharmacological and genetic findings.

Negative glucocorticoid receptor response elements and their role in glucocorticoid action.

The glucocorticoid receptor (GR) belongs to the steroid hormone receptor subclass of nuclear receptors and controls physiological processes through activation and repression of specific target genes. The ligand-activated receptor dimer activates gene expression by binding to specific DNA sequences (glucocorticoid response element, GRE) in the promoter regions of glucocorticoid-regulated genes. In contrast to the regulation of these classical GREs, the repression of negatively regulated target genes is mediated by negative GREs (nGRE), composite GREs or by transrepression. Due to their broad therapeutic spectrum and superior therapeutic effects glucocorticoids (GCs) are the most effective drugs used for the treatment of acute and chronic inflammatory diseases. Unfortunately, long term systemic therapy with GCs is restricted due to their metabolic side effects. It is assumed that transrepression of transcription factors such as AP-1 and NF-kappa B is the main mechanism by which glucocorticoids mediate their anti-inflammatory activity, whereas the side effects of GCs are mainly mediated by GR-DNA-interaction either by activation or by negative regulation of gene expression. While trans-repression has been characterized in detail, the molecular mechanisms of DNA-dependent cis-repression remain unclear. In this review, we focus on current knowledge about nGRE-mediated target gene repression and the relevance and function of these genes for glucocorticoid action. Negative GREs contribute to the regulation of the hypothalamic-pituitary-adrenal (HPA) axis (POMC and CRH), bone (osteocalcin) and skin (keratins) function, inflammation (IL-1beta), angiogenesis (proliferin) and lactation (prolactin). The discovery of the underlying mechanisms, especially the comparison to positive GREs and trans-repression may help in the future to discover and analyze novel selective GR agonists.

Dexamethasone Rapidly Induces a Novel Ras Superfamily Member-related Gene in AtT-20 Cells

Differential display was used to identify a new Ras superfamily gene (Dexras1) induced by dexamethasone (Dex) in AtT-20 cells. Treatment of AtT-20 cells with Dex for 30 min resulted in increased mRNA for Dexras1; the highest concentrations appeared after 2 h of treatment. The gene was also identified in mouse heart, brain, liver, and kidney and furthermore was induced in these tissues after Dex treatment. The deduced protein shows regions of homology characteristic of members of the Ras superfamily of small GTPases. Highest homology (36% identity, 57% positives) was found with human Rap-2b, followed closely by a number of other Ras subfamily members, suggesting that Dexras1 is probably a member of the Ras subfamily of GTPases (members include Ras and Rap). Dexras1 is the first Ras superfamily member identified that is induced in response to steroids. The function of this gene is unknown; however, its wide distribution and rapid induction by Dex suggests the possibility of a role in glucocorticoid action in a variety of tissues.

Integration of multiple signals through a complex hormone response unit in the phosphoenolpyruvate carboxykinase gene promoter.

Transcription of the phosphoenolpyruvate carboxykinase gene is stimulated by glucocorticoids, retinoic acid, and cAMP and is dominantly inhibited by insulin and phorbol esters. The glucocorticoid response is mediated by a complex regulatory unit that consists of two glucocorticoid receptor (GR) binding sites (GR1 and GR2) and two adjacent accessory factor elements (AF1 and AF2). Deletion of either the AF1 or the AF2 element results in a 50-75% reduction of the glucocorticoid response. In addition to their accessory role in glucocorticoid action, the AF1 and AF2 elements mediate retinoic acid and insulin/phorbol ester effects, respectively. Site-directed mutagenesis was performed on AF1 and AF2 to precisely locate the sequences responsible for accessory activity in each element. The glucocorticoid accessory activity of the AF1 element maps to the same 12-base pair sequence (TGACCTTTGGCC) involved in the response of the PEPCK gene to retinoic acid. The glucocorticoid accessory activity of the AF2 region maps to the same 10-base pair sequence (TGGTGTTTTG) responsible for mediating the insulin and phorbol ester responses through this element. The AF1 and AF2 elements bind different sets of nuclear proteins, and this binding is not qualitatively or quantitatively affected by treatment of the rat H4IIE hepatoma cells with retinoic acid (AF1) or insulin (AF2). AF2 functions in a heterologous context (a consensus glucocorticoid response element and the thymidine kinase promoter), whereas AF1 functions in this context only if the retinoic acid receptor is overexpressed in the cells. These results show that the AF1 and AF2 elements affect the glucocorticoid response through different protein DNA interactions, and that a small sequence in each serves multiple functions. Together with GR1 and GR2, they form a complex hormone response unit which provides an integrated response of the phosphoenolpyruvate carboxykinase gene to a variety of positive and negative signals.

Diseases Associated with Defects in Vitamin B6 Metabolism or Utilization

It is clear that many diseases are known to involve defects in vitamin B6 metabolism, but that even more await definitive studies. Furthermore, some functions of vitamin B6, such as its role in glucocorticoid action (21), have been discovered so recently that the medical implications have not yet been fully explored.

Deuterium isotope effects on the rates of steroid--glucocorticoid receptor interactions.

Rate constants of association and dissociation of several steroids to and from glucocorticoid receptor protein of chick thymus cytosol were determined in water and deuterium oxide. Substitution of deuterium for hydrogen did not influence association rate constants. Dissociation rate constants decreased about twofold in deuterium oxide in case of steroids containing an 11-beta-hydroxyl group but remained unchanged if the steroid had no hydroxyl or had an alpha-hydroxyl group at position 11. Presence of molybdate ions decreased but did not abolish the deuterium isotope effect. These findings suggest that the 11-beta-hydroxyl group, known to be present in every optimal glucocorticoid agonist molecule, participates in a kinetically relevant hydrogen bond, and that this hydrogen bond may have a role in glucocorticoid action.