Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Vakili, Hana; Jin, Yan; Cattini, Peter A.

doi:10.1074/jbc.m112.380949

Cited by 15 publications

(29 citation statements)

References 72 publications

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“…sequences revealed the presence of an E-box element that was not present in equivalent mGh DNA (34). We provide evidence that these sequences have the capacity to bind the E-box factors Bmal1 and Clock and transactivate the hGH1 promoter, using EMSA, ChIP, and transient transfection assays.…”

Section: Discussionmentioning

confidence: 90%

“…Human GH Promoter E-box Supports Bmal1/Clock Heterodimer Binding-We showed previously that the hGH1 promoter region contains a palindromic hexanucleotide (5Ј-CACGTG-3Ј) E-box element at position Ϫ264 to Ϫ259 (34). This E-box is located within the chromatin loop region linking hGH1 promoter and HS I/II regions that is required for hGH1 activation and efficient postnatal expression (26) but is not present in the same region of mGh sequences (34).…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, mGH RNA levels showed no significant oscillation over the same 26-h period. This difference might be related to the E-box element, with 5Ј-CACGTG-3Ј at its core, located in the hGH1 promoter region that is absent from equivalent mGh sequences (34). Efficient postnatal expression and even activation of hGH1 is linked to pituitary specific transcription factor Pit-1 binding, at both the promoter and remotely 14.5 kb upstream at HS I/II within the hGH1 LCR (50).…”

Section: Discussionmentioning

confidence: 99%

“…Animals were housed with ad libitum access to food and water in an environmentally controlled room maintained on a 12-h light/dark cycle with lights on at zeitgeber time (ZT 0; which refers to the number of hours after the light phase onset of 6 a.m. and lights off at ZT 12 or 6 p.m.). Control regular chow diet (CD; fat, 26 kcal%; carbohydrate, 54 kcal%; protein, 20 kcal% from Prolab-RHM 3000) or high fat diet (HFD; fat, 60 kcal%; carbohydrate, 20 kcal%; protein, 20 kcal% from Research Diets, New Brunswick, NJ) was supplied as palatable pellets for 3 days to 4-week-old male mice (16,34). The mice were maintained on their respective diets until time of euthanization (cervical dislocation) and assay.…”

Section: Methodsmentioning

confidence: 99%

“…Unlike hGH1, the endogenous mGH gene (mGh) displayed no negative response to the hyperinsulinemic conditions induced by acute excess caloric in transgenic and wild type CD1 mice in vivo (33). An explanation for this differential response could relate to the presence of an E-box DNA element in the proximal hGH1 promoter region that is absent from equivalent mGh promoter DNA (34). Furthermore, the presence of this E-box element offers a potential target for Bmal1 and Clock proteins.…”

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confidence: 99%

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Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle. Analysis of hGH1 promoter sequences revealed an enhancer motif (E-box) element that binds the circadian transcriptional machinery (Bmal1 and Clock). Furthermore, Bmal1/Clock were able to transactivate the hGH1 promoter, and mutation of this E-box element adversely affected basal activity after gene transfer. The ability of Bmal1 to bind the hGH1 promoter region containing the E-box element was confirmed in the hGH1 transgenic mouse pituitary in situ. Occupancy was reduced in mice fed a high fat diet during the light (inactive) stage of the daily cycle in mice and corresponded to a decrease in hGH1 RNA levels. The decreases in occupancy and RNA levels were not seen, however, during the dark (active) stage. A chromatin loop required for efficient postnatal hGH1 expression was negatively affected by the high fat diet in the light but not dark stage similar to the pattern observed with Bmal1 association with the promoter region. This is the first evidence that hGH synthesis follows a diurnal rhythm and of dynamic associations of the circadian machinery with a component of a chromosomal structure of the hGH1 locus that is essential for efficient expression.

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Section: Discussionmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Vakili¹,

Jin

Cattini

2016

Journal of Biological Chemistry

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Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury

Xia

Abais

et al. 2013

Naunyn-Schmiedeberg's Arch Pharmacol

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The present study investigated the protective role of growth hormone (GH) against hyperhomocysteinemia (hHcys)-induced activations of reactive oxygen species (ROS)/hypoxia-inducible factor (HIF)-1α, epithelial-mesenchymal transition (EMT) and consequent glomerular injury. A hyperhomocysteinemia (hHcys) model was induced by folate free (FF) diet in mice. The urine protein excretion significantly increased while plasma GH levels dramatically decreased in hHcys. Real time RT-PCR showed that GH receptor (GHR) level increased in the cortex of hHcys mice, which mainly occurred in podocytes as shown by confocal microscopy. Recombinant mouse growth hormone (rmGH) treatment (0.02 mg/kg, once a day for 6 weeks) significantly restored the plasma GH, inhibited GHR up-regulation and attenuated proteinuria. Correspondingly, rmGH treatment also blocked hHcys-induced decrease in the expression of podocin, a podocyte slit diaphragm molecule, and inhibited the increases in the expression of desmin, a podocyte injury marker. It was also demonstrated that in hHcys the expression of epithelial markers, p-cadherin and ZO-1, decreased, while the expression of mesenchymal markers, FSP-1 and α-SMA, increased in podocytes, which together suggest the activation of EMT in podocytes. NADPH oxidase (Nox)-dependent superoxide anion (O2·−) and HIF-1α level in the hHcys mice cortex was markedly enhanced. These hHcys-induced EMT enhancement and Nox-dependant O2·−/HIF-1α activation were significantly attenuated by rmGH treatment. HIF-1α level increased in Hcys-treated cultured podocytes, which were blocked by rmGH treatment. Meanwhile, Hcys-induced EMT in cultured podocytes was significantly reversed by HIF-1α siRNA. All these results support the view that GH ameliorates hHcys-induced glomerular injury by reducing Nox-dependent O2·−/HIF-1α signal pathway and EMT.

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Endoscopic therapy and curative effect in pituitary adenoma patients complicated by acromegalic cardiomyopathy

Zhou

Zha

et al. 2017

Neurosurg Rev

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The study aimed to retrospectively analyze the clinical characteristics of patients with pituitary adenomas complicated by acromegalic cardiomyopathy and to evaluate the effect of endoscopic surgery. Eighty-six pituitary adenoma patients complicated by acromegalic cardiomyopathy who were treated with endoscopic surgery in the First Affiliated Hospital of Soochow University from January 2010 to December 2016 were enrolled. We noted patient clinical characteristics and explored the relationships with surgical treatment. Before and after surgery, all patients underwent an examination of pituitary endocrinology, brain magnetic resonance (MR), and echocardiography. The serum levels of growth hormone (GH), left ventricular end-diastolic diameter (LVIDd), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (EF), and mitral valve (E/A ratio) were examined with non-invasive methods, and the results were compared. Of the 86 patients, there were 23 with microadenomas, 27 with large adenomas, and 36 with giant adenomas. There were 28 patients with invasive adenomas and 58 with non-invasive adenomas. The pre-operative mean GH level was 71.23 ± 3.29 μg/L, which was positively correlated with tumor volume (r = 0.751, P < 0.01). Via trans-sphenoidal endoscopic pituitary adenoma resection, 51 patients underwent total tumor resections, 25 underwent subtotal resections, 8 underwent major part resections, and 2 underwent partial resections. After surgery, the GH mean level was 3.81 ± 1.03 μg/L, which was significantly different (t = 3.72, P < 0.01) from the pre-operative level. Cardiac function indices, including LVIDd, IVST, LVPWT, E/A, and EF, were significantly improved. The long-term curative rate was 39.17% and the remission rate was 77.29%. For pituitary adenoma patients complicated by acromegalic cardiomyopathy, endoscopic surgery resulted in a good curative effect and the growth hormone levels were maintained, which can significantly improve cardiac structure and function.

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Negative Regulation of Human Growth Hormone Gene Expression by Insulin Is Dependent on Hypoxia-inducible Factor Binding in Primary Non-tumor Pituitary Cells

Cited by 15 publications

References 72 publications

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake

Protective role of growth hormone against hyperhomocysteinemia-induced glomerular injury

Endoscopic therapy and curative effect in pituitary adenoma patients complicated by acromegalic cardiomyopathy

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