11ß-hydroxysteroid dehydrogenase type 1 has no effect on survival during experimental malaria but affects parasitemia in a parasite strain-specific manner.

Malaria is a global disease associated with considerable mortality and morbidity. An appropriately balanced immune response is crucial in determining the outcome of malarial infection. The glucocorticoid (GC) metabolising enzyme, 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1) converts intrinsically inert GCs into active GCs. 11ß-HSD1 shapes endogenous GC action and is immunomodulatory. We investigated the role of 11ß-HSD1 in two mouse models of malaria. 11ß-HSD1 deficiency did not affect survival after malaria infection, but it increased disease severity and parasitemia in mice infected with Plasmodium chabaudi AS. In contrast, 11ß-HSD1 deficiency rather decreased parasitemia in mice infected with the reticulocyte-restricted parasite Plasmodium berghei NK65 1556Cl1. Malaria-induced antibody production and pathology were unaltered by 11ß-HSD1 deficiency though plasma levels of IL-4, IL-6 and TNF-α were slightly affected by 11ß-HSD1 deficiency, dependent on the infecting parasite. These data suggest that 11ß-HSD1 is not crucial for survival of experimental malaria, but alters its progression in a parasite strain-specific manner.

Macrophage 11ß-HSD-1 deficiency promotes inflammatory angiogenesis.

11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11ß-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11ß-HSD1 deficiency or inhibition. However, 11ß-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11ß-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11ß-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11ß-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11ß-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11ß-HSD1 in macrophages may be beneficial in tissue repair.

Forebrain-Specific Transgene Rescue of 11ß-HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain-Derived Neurotrophic Factor mRNA Levels in Aged 11ß-HSD1 Deficient Mice.

Mice lacking the intracellular glucocorticoid-regenerating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) are protected from age-related spatial memory deficits. 11ß-HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11ß-HSD1 may underlie the improved memory in aged 11ß-HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11ß-HSD1 deficient mice. In the present study, transgenic mice with forebrain-specific overexpression of 11ß-HSD1 (Tg) were intercrossed with global 11ß-HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11ß-HSD1 activity on spatial memory in aged mice. Transgene-mediated delivery of 11ß-HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y-maze but not spatial learning in the watermaze. Brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild-type mice. Rescue of forebrain 11ß-HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild-type mice. These findings indicate that 11ß-HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild-type mice, although 11ß-HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.

11ß-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11ß-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle. The inflammatory regulation and functional consequences of 11ß-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11ß-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11ß-HSD1 null background. 11ß-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11ß-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-α (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11ß-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-α, and interferon-γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11ß-11ß-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11ß-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11ß-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-α-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

11-ß hydroxysteroid type 1 knockout mice display an antidepressant-like phenotype in the forced swim test.

OBJECTIVE: 11ß-dehydroxysteroid dehydrogenase (HSD) types 1 and 2, enzymes are involved in the activation and inactivation of glucocorticoids in vivo, respectively. Indirect evidence implicates two enzymes in the aetiology of depression but no study has directly assessed the potential role of 11 ß-HSD1 in animal tests. METHODS: We assessed 11 ß-HSD1 knockout mice in the forced swim test (FST), tail suspension test (TST) and for locomotor activity. RESULTS: Genetic ablation of the 11ß-HSD1 gene results in an antidepressant-like phenotype in the FST; the most widely utilised animal test of antidepressant activity, but not in the related TST. This may be related to the different biological substrates underlying these tests. The decreased FST immobility was not due to alterations in general activity. CONCLUSIONS: Taken together these results suggest that 11ß-HSD1 may play an important role in depression-related behaviours and further studies are necessary to fully characterise its role in such behaviour.

Cardiomyocyte and Vascular Smooth Muscle-Independent 11ß-Hydroxysteroid Dehydrogenase 1 Amplifies Infarct Expansion, Hypertrophy, and the Development of Heart Failure After Myocardial Infarction in Male Mice.

Global deficiency of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11ß-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11ß-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11ß-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11ß-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11ß-HSD1-deficient mice had reduced infarct size (34.7 ± 2.1% left ventricle [LV] vs 44.0 ± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 ± 2.5% vs 24.7 ± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 ± 0.01 vs 0.21 ± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and ß-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11ß-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11ß-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11ß-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease.

11ß-hydroxysteroid dehydrogenase 1 specific inhibitor increased dermal collagen content and promotes fibroblast proliferation.

Glucocorticoids (GCs) are one of the most effective anti-inflammatory drugs for treating acute and chronic inflammatory diseases. However, several studies have shown that GCs alter collagen metabolism in the skin and induce skin atrophy. Cortisol is the endogenous GC that is released in response to various stressors. Over the last decade, extraadrenal cortisol production in various tissues has been reported. Skin also synthesizes cortisol through a de novo pathway and through an activating enzyme. 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is the enzyme that catalyzes the conversion of hormonally inactive cortisone to active cortisol in cells. We previously found that 11ß-HSD1 negatively regulates proliferation of keratinocytes. To determine the function of 11ß-HSD1 in dermal fibroblasts and collagen metabolism, the effect of a selective 11ß-HSD1 inhibitor was studied in mouse tissues and dermal fibroblasts. The expression of 11ß-HSD1 increased with age in mouse skin. Subcutaneous injection of a selective 11ß-HSD1 inhibitor increased dermal thickness and collagen content in the mouse skin. In vitro, proliferation of dermal fibroblasts derived from 11ß-HSD1 null mice (Hsd11b1(-/-) mice) was significantly increased compared with fibroblasts from wild-type mice. However, in vivo, dermal thickness of Hsd11b1(-/-) mice was not altered in 3-month-old and 1-year-old mouse skin compared with wild-type mouse skin. These in vivo findings suggest the presence of compensatory mechanisms in Hsd11b1(-/-) mice. Our findings suggest that 11ß-HSD1 inhibition may reverse the decreased collagen content observed in intrinsically and extrinsically aged skin and in skin atrophy that is induced by GC treatment.

Impaired oxidoreduction by 11ß-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; however, biomarkers to assess its activity in vivo are still lacking. Recent in vitro experiments suggested that human 11ß-HSD1 metabolizes the secondary bile acid 7-oxolithocholic acid (7-oxoLCA) to chenodeoxycholic acid (CDCA) and minor amounts of ursodeoxycholic acid (UDCA). Here, we provide evidence from in vitro and in vivo studies for a major role of 11ß-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11ß-HSD1-deficient mice were devoid of 7-oxoLCA oxidoreductase activity. Importantly, circulating and intrahepatic levels of 7-oxoLCA and its taurine conjugate were significantly elevated in mouse models of 11ß-HSD1 deficiency. Moreover, comparative enzymology of 11ß-HSD1-dependent oxidoreduction of 7-oxoLCA revealed that the guinea-pig enzyme is devoid of 7-oxoLCA oxidoreductase activity. Unlike in other species, 7-oxoLCA and its glycine conjugate are major bile acids in guinea-pigs. In conclusion, the oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11ß-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11ß-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11ß-HSD1 activity.

Mast cells express 11ß-hydroxysteroid dehydrogenase type 1: a role in restraining mast cell degranulation.

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). Here we show expression and activity of 11ß-HSD1, but not 11ß-HSD2, in mouse mast cells with 11ß-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11ß-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11ß-HSD1-deficient than control mice. These findings suggest that 11ß-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses.

11ß-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis.

11ß-Hydroxysteroid dehydrogenase type-1 (11ß-HSD1) converts inert cortisone into active cortisol, amplifying intracellular glucocorticoid action. 11ß-HSD1 deficiency improves cardiovascular risk factors in obesity but exacerbates acute inflammation. To determine the effects of 11ß-HSD1 deficiency on atherosclerosis and its inflammation, atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice were treated with a selective 11ß-HSD1 inhibitor or crossed with 11ß-HSD1-KO mice to generate double knockouts (DKOs) and challenged with an atherogenic Western diet. 11ß-HSD1 inhibition or deficiency attenuated atherosclerosis (74-76%) without deleterious effects on plaque structure. This occurred without affecting plasma lipids or glucose, suggesting independence from classical metabolic risk factors. KO plaques were not more inflamed and indeed had 36% less T-cell infiltration, associated with 38% reduced circulating monocyte chemoattractant protein-1 (MCP-1) and 36% lower lesional vascular cell adhesion molecule-1 (VCAM-1). Bone marrow (BM) cells are key to the atheroprotection, since transplantation of DKO BM to irradiated ApoE-KO mice reduced atherosclerosis by 51%. 11ß-HSD1-null macrophages show 76% enhanced cholesterol ester export. Thus, 11ß-HSD1 deficiency reduces atherosclerosis without exaggerated lesional inflammation independent of metabolic risk factors. Selective 11ß-HSD1 inhibitors promise novel antiatherosclerosis effects over and above their benefits for metabolic risk factors via effects on BM cells, plausibly macrophages.

11ß-Hydroxysteroid dehydrogenase type 1 contributes to the regulation of 7-oxysterol levels in the arterial wall through the inter-conversion of 7-ketocholesterol and 7ß-hydroxycholesterol.

The atherogenic 7-oxysterols, 7-ketocholesterol (7-KC) and 7ß-hydroxycholesterol (7ßOHC), can directly impair arterial function. Inter-conversion of 7-KC and 7ßOHC has recently been shown as a novel role for the glucocorticoid-metabolizing enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Since this enzyme is expressed in vascular smooth muscle cells, we addressed the hypothesis that inter-conversion of 7-KC and 7ßOHC by 11ß-HSD1 may contribute to regulation of arterial function. Incubation (4-24 h) of aortic rings with either 7-KC (25 µM) or 7ßOHC (20 µM) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation. In contrast, exposure to 7-KC (but not to 7ßOHC) attenuated noradrenaline-induced contraction (E(max)) after 4 h (0.78 ± 0.28 vs 0.40 ± 0.08 mN/mm; p < 0.05) and 24 h (2.28 ± 0.34 vs 1.56 ± 0.48 mN/mm; p < 0.05). Both 7-oxysterols were detected by GCMS in the aortic wall of chow-fed C57Bl6/J mice, with concentrations of 7-KC (1.41 ± 0.81 ng/mg) higher (p = 0.05) than 7ßOHC (0.16 ± 0.06 ng/mg). In isolated mouse aortic rings 11ß-HSD1 was shown to act as an oxo-reductase, inter-converting 7-KC and 7ßOHC. This activity was lost in aorta from 11ß-HSD1(-/-) mice, which had low oxysterol levels. Renal homogenates from 11ß-HSD1(-/-) mice were used to confirm that the type 2 isozyme of 11ß-HSD does not inter-convert 7-KC and 7ßOHC. These results demonstrate that 7-KC has greater effects than 7ßOHC on vascular function, and that 11ß-HSD1 can inter-convert 7-KC and 7ßOHC in the arterial wall, contributing to the regulation of 7-oxysterol levels and potentially influencing vascular function. This mechanism may be important in the cardioprotective effects of 11ß-HSD1 inhibitors.

Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11ß-HSD1 and H6PDH.

Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11ß-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11ß-HSD1 is implicated in the development of obesity, and selective 11ß-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11ß-HSD1. We assessed biomarkers for allele combinations of 11ß-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11ß-HSD1 KO and double KO (DKO) adrenals were ~30% larger than WT - indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and ~1.5-fold higher in 11ß-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11ß-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11ß-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11ß-HSD1/H6PDH deficiency.

11ß-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice.

Glucocorticoids profoundly influence immune responses, and synthetic glucocorticoids are widely used clinically for their potent antiinflammatory effects. Endogenous glucocorticoid action is modulated by the two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). In vivo, 11ß-HSD1 catalyzes the reduction of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, thereby increasing intracellular glucocorticoid levels. 11ß-HSD2 catalyzes the reverse reaction, inactivating intracellular glucocorticoids. Both enzymes have been postulated to modulate inflammatory responses. In the K/BxN serum transfer model of arthritis, 11ß-HSD1-deficient mice showed earlier onset and slower resolution of inflammation than wild-type controls, with greater exostoses in periarticular bone and, uniquely, ganglion cysts, consistent with greater inflammation. In contrast, K/BxN serum arthritis was unaffected by 11ß-HSD2 deficiency. In a distinct model of inflammation, thioglycollate-induced sterile peritonitis, 11ß-HSD1-deficient mice had more inflammatory cells in the peritoneum, but again 11ß-HSD2-deficient mice did not differ from controls. Additionally, compared with control mice, 11ß-HSD1-deficient mice showed greater numbers of inflammatory cells in pleural lavages in carrageenan-induced pleurisy with lung pathology consistent with slower resolution. These data suggest that 11ß-HSD1 limits acute inflammation. In contrast, 11ß-HSD2 plays no role in acute inflammatory responses in mice. Regulation of local 11ß-HSD1 expression and/or delivery of substrate may afford a novel approach for antiinflammatory therapy.

Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11betaHSD1-deficient mice post-MI.

AIMS: Mice unable to locally regenerate corticosterone due to deficiency of 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) have enhanced angiogenesis during acute myocardial infarct healing. The present study investigates the hypotheses that in these mice (i) inflammation and angiogenic signalling are promoted and (ii) longer-term remodelling and function are improved. METHODS AND RESULTS: Myocardial infarction (MI) was induced by coronary artery ligation in 11ßHSD1(-/-) and wild-type (C57BL/6) mice. Studies were terminated 2, 4, 7, and 28 days post-surgery. Increased vessel density (CD31 immunoreactivity) on the infarct border was confirmed 7 days after MI in 11ßHSD1(-/-) hearts (P < 0.05) and was accompanied by improved ejection fraction (ultrasound) compared with C57BL/6. During wound healing, recruitment of neutrophils (at 2 days after MI) and macrophages (from 4 days after MI) and expression of monocyte-chemoattractant protein-1 was increased in 11ßHSD1(-/-) compared with C57BL/6 hearts (P < 0.05). Recruitment of alternatively activated YM1-positive macrophages was particularly enhanced in the period preceding increased vessel density and was accompanied by increased expression of pro-angiogenic IL-8. By 28 days post-MI, when the infarct scar had matured, higher vessel density was maintained in 11ßHSD1(-/-) hearts and vessels were smooth-muscle coated. Infarct scars were thicker (P < 0.001) in 11ßHSD1(-/-) compared with C57BL/6 hearts and ejection fraction was higher (P < 0.05). CONCLUSION: Increased vessel density in healing infarcts of mice deficient in 11(-/-)HSD1 follows recruitment of pro-reparative macrophages and increased pro-angiogenic signalling. Mature infarcts show less thinning and cardiac function is improved relative to wild-type mice, suggesting that 11ßHSD1 may be a novel therapeutic target after MI.

11beta-hydroxysteroid dehydrogenase type 1 and obesity.

The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing's syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects - despite the opposing plasma glucocorticoid profiles of Cushing's and idiopathic metabolic syndrome - remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11beta -hydroxysteroid dehydrogenase type 1 (11beta -HSD1). In order to determine whether elevated tissue 11beta -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11beta -HSD1 in adipose tissue or liver were made. Adipose-selective 11beta -HSD1 transgenic mice exhibited elevated intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11beta -HSD1 in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hypertension and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective 11beta -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment of the metabolic syndrome. Further, a transgenic model of therapeutic 11beta -HSD1 inhibition, 11beta -HSD1 gene knock-out (11beta -HSD1-/-) mice, exhibited improved glucose tolerance, a 'cardioprotective' lipid profile, reduced weight gain and visceral fat accumulation with chronic high-fat feeding. Recent evidence further suggests that high fat-mediated downregulation of adipose 11beta -HSD1 may be an endogenous pathway that underpins adaptive disease resistance in genetically predisposed mouse strains. This mechanism could feasibly make up a genetic component of innate obesity resistance in humans. The efficacy of 11beta -HSD1 inhibitors has recently been extended to include increased energy expenditure and reduction of arteriosclerosis, and therefore may be of significant therapeutic value in the metabolic syndrome, with complementary effects upon liver adipose tissue, muscle, pancreas and plaque-prone vessels.

Macrophages from 11beta-hydroxysteroid dehydrogenase type 1-deficient mice exhibit an increased sensitivity to lipopolysaccharide stimulation due to TGF-beta-mediated up-regulation of SHIP1 expression.

11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) performs end-organ metabolism of glucocorticoids (GCs) by catalyzing the conversion of C(11)-keto-GCs to C(11)-hydroxy-GCs, thereby generating activating ligands for the GC receptor. In this study, we report that 11betaHSD1(-/-) mice are more susceptible to endotoxemia, evidenced by increased weight loss and serum TNF-alpha, IL-6, and IL-12p40 levels following LPS challenge in vivo. Peritoneal and splenic macrophage (splnMphi) from these genetically altered mice overproduce inflammatory cytokines following LPS stimulation in vitro. Inflammatory cytokine overexpression by 11betaHSD1(-/-) splnMphi results from an increased activation of NF-kappaB- and MAPK-signaling cascades and an attenuated PI3K-dependent Akt activation. The expression of SHIP1 is augmented in 11betaHSD1(-/-) Mphi and contributes to inflammatory cytokine production because overexpression of SHIP1 in primary bone marrow Mphi (BMMphi) leads to a similar type of hyperresponsiveness to subsequent LPS stimulation. 11betaHSD1(+/+) and 11betaHSD1(-/-) BMMphi responded to LPS similarly. However, 11betaHSD1(-/-) BMMphi derived in the presence of elevated GC levels up-regulated SHIP1 expression and increased their capacity to produce inflammatory cytokines following their activation with LPS. These observations suggest the hyperresponsiveness of 11betaHSD1(-/-) splnMphi results from myeloid cell differentiation in the presence of moderately elevated GC levels found within 11betaHSD1(-/-) mice. GC-conditioning of BMMphi enhanced SHIP1 expression via up-regulation of bioactive TGF-beta. Consistently, TGF-beta protein expression was increased in unstimulated CD11b(-) cells residing in the BM and spleen of 11betaHSD1(-/-) mice. Our results suggest that modest elevations in plasma GC levels can modify the LPS responsiveness of Mphi by augmenting SHIP1 expression through a TGF-beta-dependent mechanism.

Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.

Central obesity is associated with type 2 diabetes mellitus, hypertension and dyslipidaemia. This cluster of risk factors is known as the metabolic syndrome, and also occurs in people with primary glucocorticoid excess (Cushing's syndrome). Exogenous glucocorticoid use also increases the risk of cardiovascular disease. Circulating glucocorticoid concentrations are tightly controlled by the hypothalamic-pituitary-adrenal axis, however tissue glucocorticoid levels are also enhanced by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity. Although plasma glucocorticoid levels are not elevated in obesity, dysregulation of 11beta-HSD1 is observed with decreased activity in the liver and increased activity in adipose tissue. 11beta-HSD1 is highly regulated, and dietary composition may be a powerful determinant of activity. Polymorphisms in the 11beta-HSD1 gene are also associated with components of the metabolic syndrome. Inhibition of this enzyme appears to be an attractive option to treat metabolic disease. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease. Trials in humans though will be the ultimate test to determine if inhibition of 11beta-HSD1 offers a new tool in the treatment of metabolic disease.

[11beta-hydroxysteroide dehydrogenases. Recent advances]. / 11beta-hydroxystéroïde déshydrogénases. Avancées récentes.

11beta-hydroxysteroide dehydrogenase (11beta-OHSD) enzymes exhibit a regulating action upon cortisol metabolism before access to its receptors. Two types of isoenzymes have been described, type 2 being the most anciently known. Type 2 11beta-OHSD, which changes cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney, that protects mineralocorticoid receptors from illicit activation by glucocorticoids. Mutations of the gene coding for this enzyme has been demonstrated in apparent mineralocorticoid excess, which induces hypertension and hypokalemia with low renin and aldosterone levels. Polymorphisms of this gene could modulate essential hypertension and also be responsible for certain forms of acquired apparent mineralocorticoid excess especially after liquorice intoxication, in hypothyroidism, Cushing syndrome, and chronic renal insufficiency. Type 1 11beta-OHSD, which changes cortisone into cortisol, is a reductase, mainly located in liver and adipose tissue. Functional defects of this enzyme have been shown in polycystic ovaries and cortisone reductase deficiency. By contrast, metabolic syndrome, corticoid-induced osteoporosis, and glaucoma are linked to a local over-activity of this enzyme. The understanding of action mechanisms of these two enzymes currently leads to 11beta-OHSD inhibitors development, therefore opening new therapeutic strategies, especially in metabolic syndrome.

11 beta-hydroxysteroid dehydrogenase type 1 induction in the arcuate nucleus by high-fat feeding: A novel constraint to hyperphagia?

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes regeneration of active intracellular glucocorticoids in fat, liver, and discrete brain regions. Although overexpression of 11 beta-HSD1 in adipose tissue causes hyperphagia and the metabolic syndrome, male 11 beta-HSD1 null (11 beta-HSD1-/-) mice resist metabolic disease on high-fat (HF) diet, but also show hyperphagia. This suggests 11 beta-HSD1 may influence the central actions of glucocorticoids on appetite and perhaps energy balance. We show that 11 beta-HSD1-/- mice express lower hypothalamic mRNA levels of the anorexigenic cocaine and amphetamine-regulated transcript and melanocortin-4 receptor, but higher levels of the orexigenic melanin-concentrating hormone mRNAs than controls (C57BL/6J) on a low-fat diet (11% fat). HF (58% fat) diet promoted transient ( approximately 8 wk) hyperphagia and decreased food efficiency in 11 beta-HSD1-/- mice and decreased melanocortin-4 receptor mRNA expression in control but not 11 beta-HSD1-/- mice. 11 beta-HSD1-/- mice showed a HF-mediated up-regulation of the orexigenic agouti-related peptide (AGRP) mRNA in the arcuate nucleus which paralleled the transient HF hyperphagia. Conversely, control mice showed a rapid (48 h) HF-mediated increase in arcuate 11 beta-HSD1 associated with subsequent down-regulation of AGRP. This regulatory pattern was unexpected because glucocorticoids increase AGRP, suggesting an alternate hyperphagic mechanism despite partial colocalization of 11 beta-HSD1 and AGRP in arcuate nucleus cells. One major alternate mechanism governing selective fat ingestion and the AGRP system is endogenous opioids. Treatment of HF-fed mice with the mu opioid agonist DAMGO recapitulated the HF-induced dissociation of arcuate AGRP expression between control and 11 beta-HSD1-/- mice, whereas the opioid antagonist naloxone given with HF induced a rise in arcuate AGRP and blocked HF-diet induction of 11 beta-HSD1. These data suggest that 11 beta-HSD1 in brain plays a role in the adaptive restraint of excess fat intake, in part by increasing inhibitory opioid tone on AGRP expression in the arcuate nucleus.

Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes.

Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) modulates cellular steroid action. 11beta-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11beta-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1, as 11beta-HSD1 mRNA, but not 11beta-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1(-/-) macrophages, and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1(-/-) mice. These data point to an early role for 11beta-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.