Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Abstract

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E 2 ) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E 2 are believed to regulate the enzyme 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11 -HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E 2 on hepatic 11 -HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1·35 mg/ h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1·44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E 2 ; concurrent administration of 4-OHA attenuated the increase in plasma E 2 concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11 -HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E 2 concentrations, significantly increased concentrations of 11 -HSD1 (34 kDa) and GR (95 kDa) proteins. 11 -HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [ + (dehydrogenase activity) respectively. 11 -HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11 -HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E 2 .

Leydig cells from neonatal pig testis abundantly express 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 and effectively inactivate cortisol to cortisone

“…It is possible that this immunoreactive band is a dimer form of type 1, which indicates a monomeric form of 34 kDa in keeping with the predicted molecular size of a cloned pig type 1 (32,192 Da). The presence of dimeric forms has been reported for the human and sheep enzyme in tissue extracts [33][34][35][36]. A significantly weaker band corresponding to a molecular weight of 49 kDa was also detected.…”

Prenatal alcohol exposure and prenatal stress differentially alter glucocorticoid signaling in the placenta and fetal brain

“…Moreover, although we did not measure fetal CORT levels in our study, previous studies have shown that basal CORT levels are lower or unchanged in PS compared to control fetuses on GD 21 (McCabe et al, 2001; Ward and Weisz, 1984; Mairesse et al, 2007). While GR is autologously regulated in adult tissues, such that GR is downregulated when glucocorticoid levels increase (Mueller and Bale, 2008; Brunton and Russell, 2010; Handa and Weiser, 2014), evidence suggests that this autologous regulation may not occur in fetal tissues, where HPA regulation is still developing (McCabe et al, 2001; Holloway et al, 2001; Gupta et al, 2003). Again, further studies on the effects of PAE and PS on HPA development are warranted.…”

Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

“…Although HPA axis hyperactivity may be responsible for the insulin resistance in LBW, alterations in HSD-1 (and GR) expression in peripheral tissues may also contribute (28,45). Increased splanchnic cortisol production [especially due to hepatic HSD-1 activity (9, 10)] has been suggested to play a role for the development of insulin resistance and obesity in humans (46,72).…”