Disease relevance of Hsd11b1

• Glucocorticoids have been implicated as pathophysiological mediators of obesity and insulin resistance and are regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) [1].
• We observed an inverse relationship between hepatic 11beta-HSD1 expression and body weight in ob/ob mice and lean littermates [1].
• Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1(-/-) mice [2].
• The importance of 11beta-HSD-1 in glucose homeostasis is suggested by the resistance of 11beta-HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses [3].
• High-fat-fed 11 beta-HSD-1(-/-) mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories [4].
• In vivo, high-fat diet-induced obesity was accompanied by increased visceral fat preadipocyte differentiation in wild-type but not 11beta-HSD1(-/-) mice [5].
• The activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications [6].

Psychiatry related information on Hsd11b1

• Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development [7].
• The results from the present study demonstrate that the innate defense mechanisms which control the progressive growth of Listeria monocytogenes in normal animals in vivo are dependent upon the active catabolism of endogenous glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) [8].

High impact information on Hsd11b1

• We created transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans [9].
• Increased adipocyte 11beta HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome [9].
• Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS [10].
• The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia [10].
• Deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension [11].

Chemical compound and disease context of Hsd11b1

• In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment [12].
• Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease [13].
• The transgenic mouse overexpressing 11beta-hydroxysteroid dehydrogenase (11beta-HSD) develops visceral obesity [14].

Biological context of Hsd11b1

• Downregulation of 11beta-HSD-1 mRNA by LXRs started after a lag period of 8 h and required ongoing protein synthesis [15].
• Remarkably, the silencing of 11beta-HSD2 gene expression coincided with the onset of 11beta-HSD1 gene expression in the labyrinth at E16.5 when moderate levels of 11beta-HSD1 mRNA were detected and maintained to E18 [16].
• Attenuation of hepatic 11beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis [17].
• These data suggest that 11beta-HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype [3].
• The presence of a functional 11beta-HSD1 provides lymphocytes with a novel intracrine regulatory mechanism that could influence such processes as lymphocyte development, effector function, and susceptibility to apoptosis [18].

Anatomical context of Hsd11b1

• 11beta-HSD-1 is particularly expressed in adipocytes and liver and appears to be causally linked to the development of type 2 diabetes and the metabolic syndrome [15].
• Addition of T0901317 to primary hepatocytes also suppressed the expression of both 11beta-hydroxysteroid dehydrogenase type 1 and phosphoenolpyruvate carboxykinase [19].
• A distinct pattern was also observed within the endometrium where the mRNA for 11beta-HSD1 was expressed in the epithelium, whereas that for 11beta-HSD2 was confined strictly to the stroma [16].
• 5. Moreover, the expression of 11beta-HSD1 and 11beta-HSD2 in the decidua exhibited a high degree of cell specificity in that the mRNA for both 11beta-HSD1 and 11beta-HSD2 was detected in the decidua-stroma but not in the compact decidua [16].
• Distinct from the profiles of 11beta-HSD1 and 11beta-HSD2 mRNA, GR protein was detectable in all tissues at all ages studied except for the thymus, salivary gland, and bone [20].

Associations of Hsd11b1 with chemical compounds

• 11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive corticosteroids into biologically active corticosteroids, thereby regulating the local concentration of active glucocorticoids, such as cortisol [15].
• 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver [21].
• Suppression of hepatic GR expression was correlated with reduced levels of glucose and corresponded to the inhibition of phosphoenolpyruvate carboxykinase mRNA and 11beta-hydroxysteroid dehydrogenase type 1-mediated synthesis of active corticosterone from inactive 11-dehydrocorticosterone in liver [19].
• Accumulating evidence suggests that the actions of glucocorticoids in target tissues are critically determined by the expression of not only the glucocorticoid receptor (GR) but also the glucocorticoid-metabolizing enzymes, known as 11beta-hydroxysteroid dehydrogenase types 1 and 2 (11beta-HSD1 and 11beta-HSD2) [20].
• These results demonstrate an enzymatic origin of species differences in 7-oxysterol metabolism, establish the origin of endogenous 7beta-OH cholesterol in humans, and point to a possible involvement of 11beta-HSD1 in atherosclerosis [22].
• The cellular trafficking of G6P therefore directly regulates 11beta-HSD1 reductase activity and provides a novel link between glucose metabolism and function of the hypothalamo-pituitary-adrenal axis [23].
• 11beta-HSD1(-/-) mice have lower plasma glucose levels, but the fall in plasma corticosterone with sucrose supplementation was similar in 11beta-HSD1(-/-) and control mice, suggesting glucose deficiency is not the main mechanism whereby basal corticosterone levels are elevated in the null mice [24].
• 11beta-HSD1 co-localised with glucagon in the periphery of murine and human islets, but not with insulin or somatostatin [25].

Regulatory relationships of Hsd11b1

• Moreover, long-term per os treatment with a synthetic LXR agonist downregulated 11beta-HSD-1 mRNA levels by approximately 50% in brown adipose tissue and liver of wild-type but not of LXRalpha(-/-)beta(-/-) mice and was paralleled by downregulation of hepatic PEPCK expression [15].
• CONCLUSIONS: Levels of 11beta-HSD1 in islets from ob/ob mice are positively regulated by DHC and could be lowered by a selective 11beta-HSD1 inhibitor and a glucocorticoid receptor antagonist [26].
• Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11beta-HSD-1 in adipose tissue [27].
• We report here that the Ke 6 gene and the 11 beta-HSD gene are regulated in the same aberrant pattern in the cpk mouse [28].
• It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11beta-HSD-1, thereby decreasing or enhancing glucose metabolism [29].

Other interactions of Hsd11b1

• In this study, we show that treatment of adipocytes derived from 3T3-L1 cells and mouse embryonic fibroblasts in vitro with synthetic or natural LXR agonists decreases mRNA expression of 11beta-HSD-1 by approximately 50%, paralleled by a significant decline in 11beta-HSD-1 enzyme activity [15].
• Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-alpha mRNA is lost in 11beta-HSD-1(-/-) mice, consistent with attenuated glucocorticoid induction [3].
• Chronic HF feeding unexpectedly caused a down-regulation of 11beta-HSD-1 in adipose tissues of both strains, despite comparable adiposity [30].
• Mice lacking 11beta-HSD-1, however, show a more subtle phenotype with reduced activation of glucocorticoid-induced processes [31].
• To elucidate the role of endogenous glucocorticoids in bone metabolism, we developed transgenic (TG) mice in which a 2.3-kb Col1a1 promoter fragment drives 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) expression in mature osteoblasts [32].

Analytical, diagnostic and therapeutic context of Hsd11b1

• METHODS: Western blotting with antiserum for 11beta-HSD1 verified the presence of 11beta-HSD1 in islets from obese ob/ob and normal C57BL/6J mice [26].
• By gel-permeation chromatography we could demonstrate that 11beta-HSD 1 is active as a dimeric enzyme [33].
• Northern blot analysis of mouse tissues demonstrated abundant 11 beta-HSD1 message in the liver, kidney and lung, with lower expression in brain subregions and gonads [34].
• We have cloned a cDNA encoding 'liver-type' 11 beta-HSD (11 beta-HSD1) from the mouse using PCR, and have determined its nucleotide sequence [34].
• Lungs from 11beta-HSD1 -/- mice had lower surfactant protein-A (mRNA and protein) levels and significant depletion of lung surfactant according to both light and electron microscopy, and also had reduced amniotic fluid lecithin/sphingomyelin ratios [35].

References