Endocrine Abstracts

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme is a tissue specific regulator of glucocorticoid action that is linked to the development of osteoporosis, inflammatory arthritis and myopathy. Systemic inhibition of 11β-HSD1 enzyme activity has been proposed as a therapeutic option in these conditions. However, 11β-HSD1 activity has also been reported to be important in regulation of the immune response and the HPA axis. We have previously demo...

We recently showed that 5α-reduced metabolites of corticosterone (B), namely 5α-dihydrocorticosterone (5αDHB) and 5α-tetrahydrocorticosterone (5αTHB), possess similar anti-inflammatory properties to B, but have lesser metabolic effects. Here, we explored the anti-inflammatory mechanisms of these 5α-reduced metabolites in vitro. Data are mean % suppression/induction, compared by one way ANOVA, *P<0.05 versus vehicle.<p class="...

Aldosterone synthesis is heritable; a single nucleotide polymorphism (SNP) in the promoter of the aldosterone synthase gene (position −344, rs1799998) has been associated with an increased plasma aldosterone levels and hypertension. However, deletion of this site has no effect on gene transcription in vitro and therefore the mechanism that links genotype with phenotype is unclear.We identified a polymorphism at position −1651 T/C (rs13...

Essential hypertension is known to have a large genetic component. Variation in the CYP11B2 gene, which encodes the aldosterone synthase enzyme, is associated with excess aldosterone production and hypertension but the causative mechanism remains elusive. miRNAs are a class of post-transcriptional regulatory molecules, implicated in cardiovascular disease, development and tumourogenesis. They act by targeting the 3′ untranslated region (UTR) of mRNAs, inhibiting t...

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, facilitating conversion of cholesterol to pregnenolone. Cholesterol, transported by steroidogenic acute regulatory protein (StAR) into the inner mitochondrial membrane, is converted by CYP11A1 into 22R-hydroxycholesterol. Subsequently, CYP11A1 converts 22R-hydroxycholesterol by 20alpha-hydroxylation and cleavage of the C20–C22 bond into pregnenolone. All pat...

Glucocorticoids (GCs) are used extensively in the treatment of inflammatory disease. Unfortunately, as GC act on virtually every organ system they also carry a broad range of serious side-effects which limits their clinical use.The structure of the bound GC strongly impacts the final conformation of the glucocorticoid receptor (GR) and thereby dictates downstream events. Designing drugs with different GR binding properties therefore offers a plausible ro...

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Differences in gene expression between omental (om) and subcutaneous (sc) adipose have been described, but molecular mechanisms underpinning differences in adipose biology are not known. Patients with glucocorticoid excess, Cushing’s syndrome, develop a phenotype characterized by central obesity. We have characterized the regulation of lipogenesis by gluco...

Inhibiting cortisol regeneration by 11β-HSD1 is a promising therapy for type two diabetes. In obesity, 11β-HSD1 activity is increased in adipose tissue but decreased in the liver, the latter putatively mediated by hyperinsulinaemia. We tested whether insulin sensitisation with metformin regulates 11β-HSD1 activity in whole body and in liver in obesity.Five obese men (age 48±5 years, BMI 39.8±3.6 kg/m2) participated in ...