Disease relevance of HSD11B1

• CONCLUSIONS/INTERPRETATION: We confirmed that adipocyte 11beta-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity [1].
• Thus, in patients with congenital deficiency of 11 beta-HSD (the syndrome of apparent mineralocorticoid excess, AME), cortisol and not aldosterone acts as a mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of the renin-angiotensin-aldosterone axis [2].
• Here we have used real-time RT-PCR to quantify expression of mRNA for 11 beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures [3].
• Apparent mineralocorticoid excess (AME) characterized by early-onset hypertension and hypokalemia is due to congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) [4].
• Two isozymes of 11 beta-hydroxysteroid dehydrogenase, types 1 and 2 (HSD11B1 and HSD11B2), are known to modulate glucocorticoid levels in other tissues and might influence circulating levels of active and inactive glucocorticoids if they were expressed in adrenal adenomas [5].

Psychiatry related information on HSD11B1

• Conclusions: Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia [6].
• A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease [7].
• The genotype was significantly associated with alcohol consumption, gamma-GTP level, and HDL cholesterol level in both males and females [8].
• HDL cholesterol across a spectrum of physical activity from quadriplegia to marathon running [9].
• The risk reduction with gemfibrozil was 78% (P = .002) among those with BMI > 26 kg/m2 and dyslipidemia (TG > or = 2.3 mmol/L and HDL cholesterol < 1.08 mmol/L) [10].

High impact information on HSD11B1

• Perhaps studies of different forms of apoB and apoE and of HDL subgroups and hyper-alpha-lipoproteinemia will explain why certain individuals develop hypercholesterolemia and premature atherosclerosis [11].
• These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity [12].
• This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability [12].
• RESULTS: The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group [13].
• METHODS: In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos [13].

Chemical compound and disease context of HSD11B1

• OBJECTIVE: Two isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyse the interconversion of cortisol to hormonally inactive cortisone; defects in the 11 beta-HSD2 isoform result in hypertension [14].
• Adjustment for age, sex, BMI, hypertension, LDL cholesterol, HDL cholesterol, uric acid, C-reactive protein, and IL-6 did not alter these findings [15].
• In addition raloxifene does not raise overall HDL (while HRT does) but does increase venous thromboembolisms [16].
• Using receiver-operating curves, cut-points for triglyceride (TG)/high-density lipoprotein (HDL) and TG level to identify overweight individuals in the lowest tertile for insulin sensitivity were determined [17].
• Infection of apoA-I-/- mice with 2x10(9) pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles [18].

Biological context of HSD11B1

• The variable adipose expression might not be a primary consequence of these HSD11B1 SNPs [1].
• No association was observed between HSD11B1 genotype and BMI in either population [19].
• 11 beta-Hydroxysteroid dehydrogenase type II in the human endometrium: localization and activity during the menstrual cycle [20].
• The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution [21].
• This review details the enzymology, molecular biology, distribution, regulation, and function of the 11 beta-HSD isozymes and highlights the clinical consequences of altered enzyme expression [21].

Anatomical context of HSD11B1

• However, weak associations between HSD11B1 genotype, increased 11beta-HSD1 activity, and W:H ratio suggest that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11beta-HSD1 activity (E to F conversion) in visceral adipose tissue [19].
• By contrast, 11 beta-HSD1 acts predominantly as a reductase in vivo, facilitating glucocorticoid hormone action in key target tissues such as liver and adipose tissue [21].
• The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) is a potent inactivator of glucocorticoids and is present in high amounts in the placental syncytiotrophoblast and sodium-transporting epithelia [20].
• We have characterized the nature and regulation of the 11 beta-HSD activity expressed in a human cytotrophoblastic cell line, the JEG-3 choriocarcinoma cell [22].
• The present study was designed to determine whether 11 beta-HSD activity was present in human adipose stromal cells, and if changes in the activity of this enzyme could influence aromatase activity [23].

Associations of HSD11B1 with chemical compounds

• Single nucleotide polymorphisms in the HSD11B1 gene were genotyped in a larger group of full-blooded Pima Indians [1].
• These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol [24].
• BACKGROUND: 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of hormonally active cortisol to inactive cortisone and is vital for dictating specificity for the mineralocorticoid receptor [2].
• Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone [25].
• The other known isoform, 11 beta-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors [26].

Physical interactions of HSD11B1

• The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) inactivates glucocorticoids and prevents them from binding to the non-selective mineralocorticoid receptor [27].
• Thus, CD36 has been reported to bind oxidized LDL (OxLDL) and acetylated LDL (AcLDL), while SR-BI also binds native LDL and HDL [28].
• LPS administered into experimental animals circulates as LPS/HDL complex and is cleared from the blood mainly into the liver and spleen [29].

Regulatory relationships of HSD11B1

• To determine whether alterations in 11 beta-HSD could influence aromatase activity, the effect of CBX (200 microM) on cortisol- and cortisone-induced changes in the conversion of androstenedione to estrone was examined [23].
• The tissue-specific distribution of the 11 beta-HSD isoforms is in keeping with their differential roles, 11 beta-HSD1 regulating glucocorticoid hormone action and 11 beta-HSD2 mineralocorticoid hormone action [30].
• In rats, GH inhibits renal and hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activities [31].
• These data, together with the recently published observation that CRH regulates adipocyte metabolism by down-regulating 11 beta-hydroxysteroid dehydrogenase, indicate that a CRH system exists within human adipose tissue [32].
• Dex induction of 11 beta HSD was half-maximal at 48 h and was blocked by glucocorticoid receptor antagonists [33].

Other interactions of HSD11B1

• 11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to inactive products and is thus thought to confer specificity for aldosterone on the type I mineralocorticoid receptor in the kidney [34].
• The urinary ratio tetrahydrocortisols/tetrahydrocortisone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P = 0.049; P = 0.018; P = 0.043) [35].
• 11 beta-Hydroxysteroid dehydrogenase 1 activity and gene expression in human adipose stromal cells: effect on aromatase activity [23].
• BMI, waist-to-hip ratio (WHR), fasting glucose, 2-h glucose, triglycerides, HDL cholesterol, LDL cholesterol, alanine aminotransferase, leptin, and adiponectin were measured at baseline [36].
• The expression of 11 beta HSD1 (which generates F from E) in somatotrophs and lactotrophs suggests an autocrine role for this isoenzyme in the glucocorticoid regulation of pituitary GH and PRL secretion [37].

Analytical, diagnostic and therapeutic context of HSD11B1

• The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 beta-hydroxysteroid dehydrogenase activity [35].
• Ishikawa cells contain an NAD dependent enzyme migrating at 41 kDa on Western blots, consistent with the presence of the glucocorticoid-inactivating enzyme 11 beta HSD2, while the NADP dependent 11 beta HSD1 is barely detectable [38].
• In order to determine whether the product of the 11 beta-HSD 1 gene was responsible for the observed 11 beta-HSD activity, total RNA extracts from these cells were subjected to Northern blot analysis using human 11 beta-HSD 1 cDNA as the probe [23].
• In this study, 11 beta-HSD1 activity and mRNA synthesis were demonstrated in primary fetal hippocampal cell cultures [39].
• Detection of 11 beta HSD type 1 and 2 immunoreactive protein was performed using fluorescence immunohistochemistry [37].

References