11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo

Mitić, Tijana; Shave, Steven; Semjonous, Nina; McNae, I.W.; Cobice, Diego; Lavery, Gareth G.; Webster, Scott P.; Hadoke, Patrick W. F.; Walker, Brian R.; Andrew, Ruth

doi:10.1016/j.bcp.2013.02.002

Cited by 30 publications

(26 citation statements)

References 49 publications

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“…However, 11β-HSD1 has other actions that may contribute to the physiological and pathophysiological outcomes reported previously. 11β-HSD1 is a multifunctional carbonyl reductase that also converts 11- and 7-oxosterols into the respective 7-hydroxylated forms and also catalyses the reduction of non-steroidal xenobiotics (Mitic et al 2013 b , Odermatt & Klusonova 2015). Studies with selective inhibitors and genetically modified mice provide further evidence for the effects of 11β-HSD1 in the regulation of cellular cholesterol flux and on bile acid homeostasis (Mitic et al 2013 a ).…”

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

“…11β-HSD1 is a multifunctional carbonyl reductase that also converts 11- and 7-oxosterols into the respective 7-hydroxylated forms and also catalyses the reduction of non-steroidal xenobiotics (Mitic et al 2013 b , Odermatt & Klusonova 2015). Studies with selective inhibitors and genetically modified mice provide further evidence for the effects of 11β-HSD1 in the regulation of cellular cholesterol flux and on bile acid homeostasis (Mitic et al 2013 a ). Oxysterols influence vascular function (Mitic et al 2013 a ), and modulation of genes involved in cellular cholesterol flux is associated with disease severity in patients after MI (Suresh et al 2014).…”

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

“…Studies with selective inhibitors and genetically modified mice provide further evidence for the effects of 11β-HSD1 in the regulation of cellular cholesterol flux and on bile acid homeostasis (Mitic et al 2013 a ). Oxysterols influence vascular function (Mitic et al 2013 a ), and modulation of genes involved in cellular cholesterol flux is associated with disease severity in patients after MI (Suresh et al 2014). These mechanisms may therefore be engaged alongside prevention of intracellular glucocorticoid regeneration when 11β-HSD1 is genetically depleted or inhibited and could contribute to any beneficial effects of drug intervention in cardiovascular pathology.…”

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

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Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

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White

Castellan

et al. 2017

Journal of Molecular Endocrinology

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Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

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Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

Section: Therapeutic Potential Of 11β-hsd1 Inhibition In Myocardial Dmentioning

confidence: 99%

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Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

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White

Castellan

et al. 2017

Journal of Molecular Endocrinology

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“…Among these are prednisone or prednisolone, as well as some 7-keto/7-hydroxy cholesterol metabolites, which are sterically similar to normal 11βHSD substrates [9,13]. Moreover, these metabolites can compete with glucocorticoids for the 11βHSDs active sites [14], which may result in alterations of net conversion rates of cortisol and cortisone, respectively, strongly depending on the concentrations of alternative substrates within a given tissue.…”

Section: β-Hydroxysteroid Dehydrogenasesmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

Schmidt

Straub

2014

Neuroimmunomodulation

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The tissue availability of active glucocorticoids (cortisol in humans) depends on their rate of synthesis from cholesterol, downstream metabolism, excretion and interconversion. The latter is mediated by the 11β-hydroxysteroid dehydrogenases (11βHSDs). In this review, we summarize the features of the two isoenzymes, 11βHSD1 and 11βHSD2, and current available experimental data related to 11βHSDs, which are relevant in the context of synovial cells in rheumatoid arthritis (RA). We conclude that due to complex feedback mechanisms inherent to the hypothalamic-pituitary-adrenal axis, currently available transgenic animal models cannot display the full potential otherwise inherent to the techniques. Studies with tissue explants, mixed synovial cell preparations, cell lines derived from synovial cells, and related primary cells or established cell lines indicate that there are relatively clear differences between the two isoenzymes. 11βHSD1 is expressed primarily in fibroblasts and osteoblasts, and may be responsible for fibroblast survival and aid in the resolution of inflammation, but it is also involved in bone damage. 11βHSD2 is expressed primarily in macrophages and lymphocytes, and may be responsible for their survival, suggesting that it is critical in chronic inflammation. The situation in synovial tissue would allow 11βHSD2-expressing cells to tap the energy resources of 11βHSD1-expressing cells. The overall properties of this local glucocorticoid interconversion system might limit therapeutic use of glucocorticoids in RA.

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“…This enzyme was later proposed to be 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), stereo-specifically converting 7kC into 7β-hydroxycholesterol (7βOHC) in humans, rats, and mice (19–21). Data from transgenic 11β-hsd1-deficient mice exhibiting an increased 7kC to 7βOHC ratio in liver tissue samples further supported these results (22).…”

mentioning

confidence: 69%

11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Beck

Inderbinen

Kanagaratnam

et al. 2019

Journal of Lipid Research

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11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo

Abstract: Graphical abstract

Cited by 30 publications

References 49 publications

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

11β-Hydroxysteroid Dehydrogenase Enzymes Modulate Effects of Glucocorticoids in Rheumatoid Arthritis Synovial Cells

11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

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