Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11β-hydroxysteroid dehydrogenase type 1) gene

Although glucocorticoid, as “gluco-” literally implies, plays an important role in maintaining the blood glucose level, excess of glucocorticoid production/action is known to cause impaired glucose tolerance and diabetes. Since 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol, is primarily expressed in the liver, an enhanced expression of the enzyme may increase the intracellular glucocorticoid level and thus increase the hepatic glucose production. In this study, we examined the effects of multiple humoral factors related to the metabolic syndrome on the transcriptional activity of 11β-HSD1 gene in hepatocytes in vitro. We found that, among the factors examined, adipocyte-derived cytokines (adipokines), like TNFα and IL-1β, potently stimulated the transcriptional activity of 11β-HSD1 gene in human HuH7 cells. In contrast, only minimal effects of other humoral factors were observed when they were used alone. Interestingly, however, when applied in combination, they synergistically enhanced the transcriptional activity of 11β-HSD1 gene. They also potentiated the effects of cytokines. Glucocorticoid receptor (GR)-dependent transcription was indeed increased even with an inactive glucocorticoid cortisone following TNFα pretreatment, indicating the enhanced intracellular conversion. Finally, PPARγ/PPARα agonists, clinically used as anti-diabetic drugs, significantly inhibited the transcriptional activity of 11β-HSD1. Altogether, our data strongly suggest that combination of the humoral factors related to the metabolic syndrome, including the adipokines, synergistically enhances the hepatic expression of 11β-HSD1 gene and causes the intracellular Cushing state in the liver by increasing the intracellular glucocorticoid level. We assume that the observed synergistic effects of these factors on 11β-HSD1 may, at least partly, explain the reason whereby accumulation of the multiple risk factors facilitates the derangement of glucose and lipid metabolism in the metabolic syndrome.