Endocrine Abstracts

The synthesis and metabolism of bile acids and steroid hormones are conflicted at several levels. We investigated potential interactions using a feeding paradigm to stimulate bile acid secretion and salivary steroid measurements to monitor post-prandial changes.The study followed a randomised cross over design; both cortisol and cortisone were measured by specific ELISAs to assess effects on 11 beta-hydroxysteroid dehydrogenase activity (11βHSD). At...

Background and aims: Previously we showed that the bioactive liquorice constituent glycyrrhetinic acid (GA) inhibits not only 11β-hydroxysteroid dehydrogenase enzymes but also the sulphation of corticosteroids by the enzyme sulphotransferase 2A1 (SULT2A1). Since pregnenolone, 17α-hydroxy-pregnenolone, deoxycorticosterone (DOC) and dehydroepiandrosterone (DHEA) are all prime substrates for SULT2A1, GA could have important effects in directing pathways of glucocorticoi...

We investigated ACTH-induced hypertension in mice by studying renal function in vivo and by analysing renal gene expression by microarray and RT PCR methods. During two weeks sc infusion with Synacthen, mean blood pressure in adult male mice increased (89±5 vs 110±2 mmHg), and plasma corticosterone, adrenal weights and drinking rate increased by 5, 2 and 2.5-fold respectively (P<0.01); renal mass was unaffected. Greater mineralocorticoid activity wa...

Renal functions in a mouse model of Cushing’s Syndrome have been characterised by analysing RNA expression complemented by immunohistochemistry studies. A microarray of kidneys from mice infused with ACTH for two weeks identified gene transcripts that were up-regulated (70) and down-regulated (49) more than two-fold. Four separate clusters of closely correlated genes (r> 0.97; P< 0.001) were investigated in more detail. One down-regulated cluster included histocom...

Background and aims: Bile acids are conserved through enterohepatic circulation, a glucocorticoid-modulated process. 11β-Hydroxysteroid dehydrogenase type-1 (11β-HSD1) converts cortisone/11-dehydrocortisone to cortisol/corticosterone, thus increasing intracellular glucocorticoid levels. 11β-HSD1 also metabolises 7-oxo-lithocholic acid, a bile acid. 11β-HSD1 is highly expressed in the liver and may alter bile acid transport through regeneration of active glu...

Background: The effects of glucocorticoids (GC) on the developing zebrafish embryo (Zfe) are poorly characterised. We have assessed the effects of pharmacological and genetic manipulation of cortisol and glucocorticoid receptors (GR) on global development and stress response during the first 120 hpf.Methods: Cortisol production was modulated by inhibiting the enzyme 11b hydroxylase using morpholino gene knockdown (MO) or incubation in the drug metyrapone...

Variation in the glucocorticoid receptor (GR) gene associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk in humans. To investigate the contribution of cardiac GR to this phenotype we have characterised adult male mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO) and have found left ventricular function to be impaired.SMGRKO mice, generated by crossing GR ‘floxed’ mice...

Glucocorticoid signalling is essential for cardiac maturation late gestation. In mice, global glucocorticoid receptor deficiency (GR−/−) severely impairs cardiac function and ultrastructure at embryonic day (E) 17.5. To dissect direct effects of GR deficiency in the heart from effects on other systems, Sm22α-Cre mice were crossed with ‘floxed’ GR mice to generate SMGRKO mice with disrupted GR signalling in cardiomyocytes and vascular smoot...

11β-Hydroxysteroid dehydrogenase type one (11β-HSD1) converts inert glucocorticoids to active forms, amplifying intracellular glucocorticoid action. 11β-HSD1 also catalyses the reduction of seven-ketocholesterol (7KC) to 7β-hydroxycholesterol (7βHC). 7KC may inhibit cholesterol biosynthesis (Brown et al. 2002). Alteration of cholesterol homeostasis is a major atherosclerotic risk factor. 11β-HSD1 deficiency/inhibition is atheroprotective ...

Background and aims: Bile acids regulate cholesterol metabolism and the digestive system. They are conserved through enterohepatic circulation, a glucocorticoid-modulated process. We investigated whether the regeneration of active glucocorticoid by 11β-hydroxysteroid dehydrogenase type one (11β-HSD1) affects bile acid release and enterohepatic transport after re-feeding.Methods: Bile acid turnover was assessed in global (Hsd11b11<...