Effect of growth hormone, insulin and dexamethasone on 11 β -hydroxysteroid dehydrogenase activity on a primary culture of rat hepatocytes

Liu, Yanjun; Nakagawa, Yuichi; Nasuda, Kaoru; Saegusa, Hirokazu; Igarashi, Y

doi:10.1016/0024-3205(96)00288-3

Cited by 44 publications

(31 citation statements)

References 26 publications

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“…This is also supported by studies on rats, where GH and insulin have been found to suppress the conversion of cortisone to cortisol (15,16). On the other hand, in vitro studies of human omental adipose cells demonstrate a dose-dependent inhibition of 11bHSD1 by insulin-like growth factor-I (IGF-I) but not GH (15,16). In a small study of hypopituitary patients this was explained as being an inhibitory effect of GH on 11bHSD1 that was maximal at very low doses and not mediated indirectly by change in circulating insulin (17).…”

Section: Introductionsupporting

confidence: 62%

“…Studies on hypopituitary patients receiving oral glucocorticoid replacement, acromegalic patients withdrawing from octreotide treatment and acromegalic patients treated surgically, indicate that growth hormone (GH) inhibits 11bHSD1 and thereby decreases the conversion of cortisone to cortisol (increased urinary cortisol/cortisone ratio) (13 -15). This is also supported by studies on rats, where GH and insulin have been found to suppress the conversion of cortisone to cortisol (15,16). On the other hand, in vitro studies of human omental adipose cells demonstrate a dose-dependent inhibition of 11bHSD1 by insulin-like growth factor-I (IGF-I) but not GH (15,16).…”

Section: Introductionsupporting

confidence: 55%

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GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration

Sigurjónsdóttir¹,

Korányi²,

Axelson³

et al. 2006

eur j endocrinol

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Objective: In the past years the interaction of GH and 11bhydroxysteroid dehydrogenase (11bHSD) in the pathogenesis of central obesity has been suggested. Design: We studied the effects of 9 months of GH treatment on 11bHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48-66 years, in a randomised, double-blind, placebo-controlled trial. Methods: Urinary steroid profile was used to estimate 11bHSD type 1 and 2 (11bHSD1 and 11bHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic -hyperinsulinaemic glucose clamp was used to assess insulin sensitivity. Results: In the GH-treated group the 11bHSD1 activity decreased transiently after 6 weeks (P , 0.01) whereas 11bHSD2 increased after 9 months of treatment (P , 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11bHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11bHSD1 and 11bHSD 2 and changes in GDR. Discussion: The study demonstrates that short-and long-term GH treatment has different effects on 11bHSD1 and 11bHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11bHSD.European Journal of Endocrinology 154 69-74

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Section: Introductionsupporting

confidence: 62%

Section: Introductionsupporting

confidence: 55%

GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration

Sigurjónsdóttir¹,

Korányi²,

Axelson³

et al. 2006

eur j endocrinol

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“…Low et al (1994) further demonstrated that continuous administration of GH to male rats (mimicking the pattern of secretion of GH in the female) suppressed 11 -HSD1 activity, whereas pulsatile administration of GH (mimicking the pattern of secretion of GH in the male) had no effect . Similarly, GH has been shown to inhibit 11 -HSD1 activity in primary cultures of rat hepatocytes (Liu et al 1996). However, Wang et al (1997) have reported increased hepatic 11 -HSD1 mRNA after the administration of oestrogen to late-gestation fetal sheep, suggesting that there may be differences in response depending upon the duration and magnitude of the oestrogen administration.…”

Section: Discussionmentioning

confidence: 99%

“…Administration of cortisol or betamethasone has been shown to stimulate hepatic expression of 11 -HSD1 mRNA and protein, and enzyme activity, in late-gestation fetal sheep liver , Sloboda et al 2001). Dexamethasone has also been shown to stimulate 11 -HSD1 activity in primary culture of rat hepatocytes (Liu et al 1996). In addition, it has been shown that expression of 11 -HSD1 is increased after occlusion of the ductus venosus and concomitant increase in plasma cortisol concentrations (Tchirikov et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

Gupta¹,

Alfaidy²,

Holloway³

et al. 2003

Journal of Endocrinology

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In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E 2 ) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E 2 are believed to regulate the enzyme 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11 -HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E 2 on hepatic 11 -HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1·35 mg/ h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1·44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E 2 ; concurrent administration of 4-OHA attenuated the increase in plasma E 2 concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11 -HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E 2 concentrations, significantly increased concentrations of 11 -HSD1 (34 kDa) and GR (95 kDa) proteins. 11 -HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [ + (dehydrogenase activity) respectively. 11 -HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11 -HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E 2 .

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“…Insulin has no effect on renal 11␤-HSD1 in diabetic rats (411). In vitro, high levels of insulin downregulate 11␤-HSD1 expression (259,316,410,731) probably through insulin-like growth factor I (IGF-1) receptors, whereas lower concentrations of insulin (too low to bind IGF-1 receptors) have no effect or modestly increase 11␤-HSD1 expression in adipocytes (52, 510). Interpretation is confounded by the use of high levels of glucose, which mimic an insulin-resistant state, and the mitogenic effects of insulin in culture which may decrease 11␤-HSD1: there is negligible 11␤-HSD1 in most proliferating cell lines.…”

Section: F 11␤-hsd1 Regulationmentioning

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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Effect of growth hormone, insulin and dexamethasone on 11 β -hydroxysteroid dehydrogenase activity on a primary culture of rat hepatocytes

Cited by 44 publications

References 26 publications

GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration

GH effect on enzyme activity of 11βHSD in abdominal obesity is dependent on treatment duration

Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

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

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