Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment

DuBois, Debra C.; Xu, Zhixin; McKay, Lorraine I.; Almon, Richard R.; Pyszcznski, Nancy; Jusko, William J.

doi:10.1016/0960-0760(95)00139-q

Cited by 34 publications

(25 citation statements)

References 22 publications

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“…This was probably an effect of acute hypercorticosteronaemia, resulting from stress immediately prior to killing, to which adrenalectomised animals would not respond. In support of this contention, liver GR mRNA down-regulation has been recorded previously within 30 min of administration of dex in vivo (16). Furthermore, an effect of sham surgery per se has been previously identified on the expression in liver of 11b-hydroxysteroid dehydrogenase type I, the enzyme responsible for re-activation of endogenous glucocorticoid (34).…”

Section: Discussionmentioning

confidence: 65%

“…Previous studies have not considered the effect of altered corticosterone concentration on GR mRNA in muscles of varying fibre type composition (18,19) or adipose depots, or the effect of such chronic manipulations on liver GR (16,17). However, down-regulation of GR provoked by addition of dex to hepatoma cells reverses within a few days (35), while the effect of adrenalectomy on hippocampal GR is abolished within 2 weeks (36), supporting the implication of this study that GR auto-regulation is a relatively acute phenomenon.…”

Section: Discussionmentioning

confidence: 99%

“…Previous in vivo studies have shown that short-term increases in glucocorticoid levels down-regulate GR mRNA in liver (16,17) and skeletal muscle (18), while adrenalectomy up-regulates GR mRNA in muscle (19), but not in liver (17). However, there is very little published information documenting GR auto-regulation in adipose tissue, or the effects of chronically altered glucocorticoid levels on GR.…”

Section: Introductionmentioning

confidence: 99%

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Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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Objective: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tissue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. Design and methods: Rats were treated with dex (100 mg/kg per day) or saline during the third week of pregnancy. In 5-8-month-old male offspring, GR expression in insulin target tissues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n ¼ 7 -8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. Results: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0:11^0:01 ratio to b-actin, vs ADX 0:22^0:02; CORT 0:23^0:02; (values expressed as means^S.E.M.), P , 0:001). Rosiglitazone reduced GR mRNA by ,30% in liver of dex-and saline-treated offspring ðP , 0:05Þ; but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0:14^0:01 vs 0:10^0:01; P ¼ 0:03). Conclusions: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Cleasby

Livingstone²,

Nyirenda³

et al. 2003

European Journal of Endocrinology

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“…The cRNA was prepared using conventional cloning methods [19,20] and then in vitro transcribed to cRNA using T7 MEGAs-cript In Vitro Transcription Kits (Ambion, Austin, TX). For QRT RT-PCR assays, specific TaqMan probes and primers were designed using PrimerExpress software (Applied Biosystems, Foster City, CA); sequences sharing homology with other rat genes were excluded.…”

Section: Hepatic Gr and Tat Mrna Measurementsmentioning

confidence: 99%

“…10) the dynamics of which are governed by MPL, to form drug-receptor complex in the cytosol (CR), which rapidly translocates to the nucleus forming DR(N). Both nuclear drug-receptor complexes act non-competitively on TAT mRNA production rate as given by, (18) (19) (20) where K d,CST is the dissociation constant for CST binding to free receptors (R) and was calculated from a quantitative structure-property relationship (QSPR) model [36]; k T is the translocation constant to account for rapid entry of CR to form CR(N). The TAT mRNA is produced at a zero-order rate (k s,TATm ) and dissipates with a first-order rate constant, k d,TATm .…”

Section: Tyrosine Aminotransferase Dynamicsmentioning

confidence: 99%

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Hazra

Pyszczynski

DuBois

et al. 2007

J Pharmacokinet Pharmacodyn

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Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60-70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/genemediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.

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Corticosteroid effects in skeletal muscle: Gene induction/receptor autoregulation

et al. 1997

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Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment

Cited by 34 publications

References 22 publications

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Corticosteroid effects in skeletal muscle: Gene induction/receptor autoregulation

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