The Role of 11ß-Hydroxysteroid Dehydrogenase 1 in Adipogenesis in Thyroid-Associated Ophthalmopathy

Tomlinson, Jeremy W.; Durrani, Omar M.; Bujalska, Iwona; Gathercole, Laura; Tomlins, Paul J.; Reuser, Tristan; Rose, Geoffrey E.; Curnow, S. John; Stewart, Paul M.; Walker, Elizabeth A.; Rauz, Saaeha

doi:10.1210/jc.2009-0873

Cited by 21 publications

(17 citation statements)

References 44 publications

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“…Primary cultures of adipocytes from thyroid-associated ophthalmopathy patients have much higher expression of 11␤-HSD1 than controls and produce a host of proinflammatory cytokines, which might underlie the increase in the enzyme, although this might merely reflect the more differentiated state of ophthalmopathy adipocytes. Cytokine production by these cells is attenuated by 11␤-HSD inhibition (710), and the enzyme plays a role in adipogenesis in retro-ocular as other sites. Any role in therapy of this challenging disorder is uncertain, but merits exploration.…”

Section: The Eyementioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

675

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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Section: The Eyementioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

675

601

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“…Similarly, in differentiated cells such as osteoblasts and adipocytes, TNFα increases 11β-HSD1 activity to enhance local GC generation (Cooper et al . 2001, Tomlinson et al . 2010).…”

Section: Discussionmentioning

confidence: 99%

TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

Doig

Bashir

Zielińska

et al. 2014

Journal of Endocrinology

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The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11b1 gene and was dependent on the NF-κB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at position −218 to −245 bp of the Hsd11b1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease.

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“…A putative role for 11β (Beta)-HSD1 in cognitive impairment is postulated along with investigations looking at the link between 11β (Beta)-HSD1 and human eye disease including thyroid eye disease [ 105 ] and glaucoma. 11β (Beta)-HSD1 inhibitors have been shown to improve cognitive function in elderly persons with T2 DM [ 106 ].…”

Section: Central Nervous System (Cns)mentioning

confidence: 99%

The Dehydrogenase Hypothesis

Woods

Tomlinson

2015

Advances in Experimental Medicine and Biology

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Circulating glucocorticoid (GC) levels are controlled by the Hypothalamo-Pituitary-Adrenal (HPA) axis, but within tissues, GC availability is controlled by the isoforms of 11β (Beta)-Hydroxysteroid Dehydrogenase 11β (Beta)-HSD that interconvert inactive cortisone and active cortisol. Two isoforms have been identified; in key metabolic target tissues (including liver and adipose), expression of 11β (Beta)-HSD1 predominates that in vivo converts cortisone to cortisol and thus amplifies local GC action. In contrast, in mineralocorticoid target tissues 11β (Beta)-HSD2 is the isoform that is most abundantly expressed. This inactivates cortisol to cortisone and offers protection for the mineralocorticoid receptor form occupation and activation by cortisol. Dysregulated 11β (Beta)-HSD1 activity has been implicated in many metabolic diseases such as obesity and diabetes and inhibition of 11β (Beta)-HSD1 represents a promising therapeutic target. Mutations within the gene encoding 11β (Beta)-HSD2 cause the Syndrome of Apparent Mineralocorticoid Excess and decreases in activity are linked to hypertension as well as impairment in placental function and neonatal growth. We will discuss the molecular biology and enzymology of 11β (Beta)-HSD and its role in normal physiology and discuss altered 11β (Beta)-HSD activity in pathological states and the potential for therapeutic targeting.

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The Role of 11ß-Hydroxysteroid Dehydrogenase 1 in Adipogenesis in Thyroid-Associated Ophthalmopathy

Abstract: Induction of 11beta-HSD1 activity and expression by inflammatory cytokines (TNF-alpha, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11beta-HSD1 may also have a role in regulating the local orbital inflammatory response.

Cited by 21 publications

References 44 publications

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

The Dehydrogenase Hypothesis

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