Modification of microsomal 11β-HSD1 activity by cytosolic compounds: Glutathione and hexose phosphoesters

McCormick, Kenneth; Wang, Xudong; Mick, Gail J.

doi:10.1016/j.jsbmb.2008.04.003

Cited by 10 publications

(11 citation statements)

References 66 publications

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“…3 shows that F6P and G6P served as excellent substrates, increasing [ 3 H]-11-deoxycortisol production 10 and 12 fold, respectively. This finding corroborates earlier evidence by our lab [29] and others [30] that both of these hexose-phosphoesters can stimulate 11βHSD1. In the case of F6P, the stimulation is indirect, that is, via conversion to G6P by microsomal isomerase [30].…”

Section: Resultssupporting

confidence: 93%

Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes

Foster

Mick

Wang

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The role of adrenal hexose-6-phosphate dehydrogenase in providing reducing equivalents to P450 cytochrome steroidogenic enzymes in the endoplasmic reticulum is uncertain. Hexose-6-phosphate dehydrogenase resides in the endoplasmic reticulum lumen and co-localizes with the bidirectional enzyme 11β-hydroxysteroid dehydrogenase 1. Hexose-6-phosphate dehydrogenase likely provides 11β-hydroxysteroid dehydrogenase 1 with NADPH electrons via channeling. Intracellularly, two compartmentalized reactions generate NADPH upon oxidation of glucose-6-phosphate: cytosolic glucose-6-phosphate dehydrogenase and microsomal hexose-6-phosphate dehydrogenase. Because some endoplasmic reticulum enzymes require an electron donor (NADPH), it is conceivable that hexose-6-phosphate dehydrogenase serves in this capacity for these pathways. Besides 11β-hydroxysteroid dehydrogenase 1, we examined whether hexose-6-phosphate dehydrogenase generates reduced pyridine nucleotide for pivotal adrenal microsomal P450 enzymes. 21-hydroxylase activity was increased with glucose-6-phosphate and, also, glucose and glucosamine-6-phosphate. The latter two substrates are only metabolized by hexose-6-phosphate dehydrogenase, indicating that requisite NADPH for 21-hydroxylase activity was not via glucose-6-phosphate dehydrogenase. Moreover, dihydroepiandrostenedione, a non-competitive inhibitor of glucose-6-phosphate dehydrogenase, but not hexose-6-phosphate dehydrogenase, did not curtail activation by glucose-6-phosphate. Finally, the most compelling observation was that the microsomal glucose-6-phosphate transport inhibitor, chlorogenic acid, blunted the activation by glucose-6-phosphate of both 21-hydroxylase and 17-hydroxylase indicating that luminal hexose-6-phosphate dehydrogenase can supply NADPH for these enzymes. Analogous kinetic observations were found with microsomal 17-hydroxylase. These findings indicate that hexose-6-phosphate dehydrogenase can be a source, but not exclusively so, of NADPH for several adrenal P450 enzymes in the steroid pathway. Although the reduced pyridine nucleotides are produced intra-luminally, these compounds may also slowly transverse the endoplasmic reticulum membrane by unknown mechanisms.

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Section: Resultssupporting

confidence: 93%

Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes

Foster

Mick

Wang

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Conversely, 11␤-reductase activity is markedly increased in patients with glycogen storage disease type 1a caused by deficiency of glucose-6-phosphatase-␣ that, in liver, competes with H6PDH for glucose-6-phosphate (748). Fructose-6-phosphate converted to glucose-6-phosphate by an ER hexose-6-phosphate isomerase (628), also increases 11␤-reductase activity in liver microsomes (449,628).…”

Section: H6pdh Determines 11␤-hsd1 Reaction Directionmentioning

confidence: 99%

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

Chapman

Holmes

Seckl

2013

Physiological Reviews

736

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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“…The adipose does not express fructokinase and fructose is converted by hexokinase to F6P [137]. An in vitro study using rat and porcine liver microsomes found that G6P and F6P but not galactose-1-phosphate, glucose-1-phosphate, and fructose-1-phosphate stimulated 11β-HSD1 oxoreductase activity [24]. Interestingly, F6P, unlike G6P, failed to increase 11β-HSD1 oxoreductase activity in porcine adipose microsomes, and the reason for this observation remains unclear.…”

Section: Effect Of Fructose On 11β-hsd1 Expression and Activitymentioning

confidence: 99%

“…Besides dietary fructose, an increased intracellular glucocorticoid production, especially in adipose tissue, has also been suggested to contribute to the pathogenesis of the MetS [20,21,22], and evidence was provided for a possible link between fructose and glucocorticoid activation [23,24,25]. The circulating and locally produced glucocorticoids have a crucial role in modulating adipocyte function as well as proliferation/differentiation [26,27].…”

Section: Introductionmentioning

confidence: 99%

Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome

et al. 2017

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The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.

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Modification of microsomal 11β-HSD1 activity by cytosolic compounds: Glutathione and hexose phosphoesters

Cited by 10 publications

References 66 publications

Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes

Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes

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

Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome

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