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Menno Hoekstra - One of the best experts on this subject based on the ideXlab platform.
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ATP-binding cassette transporter G1 deficiency is associated with mild Glucocorticoid insufficiency in mice.
Biochimica et Biophysica Acta, 2019Co-Authors: Menno Hoekstra, Amber B. Ouweneel, Joya E. Nahon, Rick Van Der Geest, Mara J. Kröner, Ronald J. Van Der SluisAbstract:Abstract Objective Since cholesterol is the sole precursor for Glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie Glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate. Methods The Adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the Adrenal Glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls. Results Overnight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P Conclusion ABCG1 deficiency is associated with mild Glucocorticoid insufficiency in mice.
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scavenger receptor class b type i mediated uptake of serum cholesterol is essential for optimal Adrenal Glucocorticoid production
Journal of Lipid Research, 2009Co-Authors: Menno Hoekstra, Theo J.c. Van Berkel, Reeni B. Hildebrand, Ying Zhao, Bart Lammers, Miranda Stitzinger, Johan Kuiper, Miranda Van EckAbstract:Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces Adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of Adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased Adrenal HDL-CE clearance from 33–58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed Adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38–52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical >4-fold increased tumor necrosis factor-α response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal Adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse Adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal Adrenal function.
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Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate Adrenal Glucocorticoid-mediated stress response to fasting
Journal of lipid research, 2008Co-Authors: Menno Hoekstra, Miranda Van Eck, Illiana Meurs, Mieke Koenders, Ruud Out, Reeni B. Hildebrand, J. Kar Kruijt, Theo J.c. Van BerkelAbstract:Receptor-mediated cholesterol uptake has been suggested to play a role in maintaining the Adrenal intracellular free cholesterol pool and the ability to produce hormones. Therefore, in the current study, we evaluated the importance of scavenger receptor class B type I (SR-BI)-mediated cholesteryl ester uptake from HDL for Adrenal Glucocorticoid hormone synthesis in vivo. No difference was observed in the plasma level of corticosterone between SR-BI-deficient and wild-type mice under ad libitum feeding conditions. Overnight fasting (∼16 h) stimulated the plasma level of corticosterone by 2-fold in wild-type mice. In contrast, no effect of fasting on plasma corticosterone levels was observed in SR-BI-deficient mice, leading to a 44% lower plasma corticosterone level compared with their wild-type littermate controls. In parallel, an almost complete depletion of lipid stores in the Adrenal cortex of fasted SR-BI-deficient mice was observed. Plasma adrenocorticotropic hormone levels were increased by 5-fold in fasted SR-BI-deficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the Glucocorticoid-responsive genes cholesterol 7α-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-α, which coincided with a 42% decreased plasma glucose level under fasting conditions. In conclusion, we show that the absence of Adrenal HDL cholesteryl ester uptake in SR-BI-deficient mice impairs the Adrenal Glucocorticoid-mediated stress response to fasting as a result of Adrenal Glucocorticoid insufficiency and attenuated liver Glucocorticoid receptor signaling, leading to hypoglycemia under fasting conditions.
Gastone G Nussdorfer - One of the best experts on this subject based on the ideXlab platform.
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orexins in the regulation of the hypothalamic pituitary Adrenal axis
Pharmacological Reviews, 2006Co-Authors: Raffaella Spinazzi, Paola G Andreis, Gian Paolo Rossi, Gastone G NussdorferAbstract:Orexin-A and orexin-B are hypothalamic peptides that act via two G protein-coupled receptors, named orexin type 1 and type 2 receptors (OX1-Rs and OX2-Rs). The most studied biological functions of orexins are the central control of feeding and sleep, but in the past few years findings that orexin system modulates the hypothalamic-pituitary-Adrenal (HPA) axis, acting on both its central and peripheral branches, have accumulated. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and median eminence and orexin receptors in pituitary corticotropes, Adrenal cortex, and medulla. Whereas the effects of orexins on Adrenal aldosterone secretion are doubtful, compelling evidence indicates that these peptides enhance Glucocorticoid production in rats and humans. This effect involves a 2-fold mechanism: 1) stimulation of the adrenocorticotropin-releasing hormone-mediated pituitary release of adrenocorticotropin, which in turn raises Adrenal Glucocorticoid secretion; and 2) direct stimulation of adrenocortical cells via OX1-Rs coupled to the adenylate cyclase-dependent cascade. The effects of orexins on catecholamine release from Adrenal medulla are unclear and probably of minor relevance, but there are indications that orexins can stimulate in vitro secretion of human pheochromocytoma cells via OX2-Rs coupled to the phospholipase C-dependent cascade. Evidence is also available that orexins enhance the growth in vitro of adrenocortical cells, mainly acting via OX2-Rs. Moreover, findings suggest that the orexin system may favor HPA axis responses to stresses and play a role in the pathophysiology of cortisol-secreting Adrenal adenomas.
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effect of luteinizing hormone releasing hormone on rat adrenocortical cells
The Journal of Steroid Biochemistry and Molecular Biology, 1997Co-Authors: Paola G Andreis, Giuliano Neri, Gastone G NussdorferAbstract:The effects of luteinizing hormone-releasing hormone (LH-RH) on the function of rat Adrenal cortex were investigated by using dispersed zona glomerulosa (capsular) and zona fasciculata-reticularis (inner) cells. LH-RH increased basal (but not adrenocorticotropic hormone (ACTH)-stimulated) corticosterone secretion of inner cells, without affecting either aldosterone or corticosterone production by capsular cells. LH-RH markedly raised basal (but not ACTH-enhanced) cyclic-AMP release by inner cells. The corticosterone secretagogue action of LH-RH was abolished by the protein kinase A inhibitor H-89. The conclusion is drawn that LH-RH specifically stimulates Adrenal Glucocorticoid secretion in rats through the activation of the adenylate cyclase signaling pathway.
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arginine vasopressin stimulates crh and acth release by rat Adrenal medulla acting via the v 1 receptor subtype and a protein kinase c dependent pathway
Peptides, 1997Co-Authors: Giuseppina Mazzocchi, Piera Rebuffat, Ludwik K Malendowicz, Cinzia Tortorella, Gastone G NussdorferAbstract:Abstract Mazzocchi, G., L. K. Malendowicz, P. Rebuffat, C. Tortorella and G. G. Nussdorfer. Arginine-vasopressin stimulates Crh and Acth release by rat Adrenal medulla, acting via the V 1 receptor subtype and a protein kinase C-dependent pathway. Peptides 18(2) 191–195, 1997.—Arginine-vasopressin (AVP) is a hypothalamic hormone that, like CRH, stimulates the pituitary release of ACTH, thereby activating Adrenal Glucocorticoid secretion. Evidence indicates that rat Adrenal medulla contains a CRH-ACTH system duplicating that existing at the hypothalamo-pituitary level and involved in the paracrine stimulation of the cortex secretion. Therefore, we investigated by RIA the effect of AVP on the release of CRH and ACTH immunoreactivities (IR) by rat Adrenal medulla in vitro. AVP concentration-dependently enhanced the release of both CRH-IR and ACTH-IR, and the effect was blocked by a selective antagonist of the V 1 subtype of AVP receptors. The CRH receptor antagonist α -helical-CRH partially reversed AVP-evoked rise in ACTH-IR release, without altering either CRH response or basal secretions of CRH and ACTH. The specific inhibitors of protein kinase C Ro31-8220 and calphostin C abolished both CRH and ACTH responses to AVP. In conclusion, our present findings suggest that AVP stimulates intramedullary the CRH-ACTH system, acting via V 1 receptors and activating protein kinase C.
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the effects of ageing on the morphology and function of the zonae fasciculata and reticularis of the rat Adrenal cortex
Cell and Tissue Research, 1992Co-Authors: Piera Rebuffat, Paola G Andreis, Giuliano Neri, Giuseppina Mazzocchi, Ludwik K Malendowicz, Anna S Belloni, S Rocco, Giuseppe Gottardo, Gastone G NussdorferAbstract:The morphological counterpart of the well-known age-dependent marked impairment of Glucocorticoid secretion of rat Adrenals was investigated by use of morphometric techniques. For this purpose 4-, 8-, 16- and 24-month-old rats were studied. Despite the notable lowering of both basal and ACTH-stimulated production of corticosterone by collagenase-dispersed inner adrenocortical cells, ACTH and corticosterone plasma concentrations displayed significant increases with ageing. Zona fasciculata (ZF) and zona reticularis (ZR) showed a notable hypertrophy in aged rats, which was due to rises in both the average volume and number of their parenchymal cells. The hypertrophy of ZF and ZR cells was in turn associated with increase in the volume of the mitochondrial compartment and proliferation of smooth endoplasmic reticulum, i.e., the two organelles involved in steroid-hormone synthesis. All these morphologic changes, conceivably due to the chronic exposure to high levels of circulating ACTH, are interpreted as a response enabling ZF and ZR to compensate for their age-dependent lowering in Glucocorticoid secretion. Stereology also demonstrated that ZF and ZR cells underwent a striking age-related lipid-droplet repletion. Lipid droplets are the intracellular stores of cholesterol esters, the obligate precursors of steroid hormones in rats. This finding is in keeping with the contention that the mechanism underlying the age-dependent decline in rat-Adrenal Glucocorticoid secretion mainly involves impairments of the utilization of intracellular cholesterol previous to its intramitochondrial transformation to pregnenolone.
Ronald J. Van Der Sluis - One of the best experts on this subject based on the ideXlab platform.
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ATP-binding cassette transporter G1 deficiency is associated with mild Glucocorticoid insufficiency in mice.
Biochimica et Biophysica Acta, 2019Co-Authors: Menno Hoekstra, Amber B. Ouweneel, Joya E. Nahon, Rick Van Der Geest, Mara J. Kröner, Ronald J. Van Der SluisAbstract:Abstract Objective Since cholesterol is the sole precursor for Glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie Glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate. Methods The Adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the Adrenal Glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls. Results Overnight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P Conclusion ABCG1 deficiency is associated with mild Glucocorticoid insufficiency in mice.
Theo J.c. Van Berkel - One of the best experts on this subject based on the ideXlab platform.
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scavenger receptor class b type i mediated uptake of serum cholesterol is essential for optimal Adrenal Glucocorticoid production
Journal of Lipid Research, 2009Co-Authors: Menno Hoekstra, Theo J.c. Van Berkel, Reeni B. Hildebrand, Ying Zhao, Bart Lammers, Miranda Stitzinger, Johan Kuiper, Miranda Van EckAbstract:Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces Adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of Adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased Adrenal HDL-CE clearance from 33–58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed Adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38–52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical >4-fold increased tumor necrosis factor-α response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal Adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse Adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal Adrenal function.
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Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate Adrenal Glucocorticoid-mediated stress response to fasting
Journal of lipid research, 2008Co-Authors: Menno Hoekstra, Miranda Van Eck, Illiana Meurs, Mieke Koenders, Ruud Out, Reeni B. Hildebrand, J. Kar Kruijt, Theo J.c. Van BerkelAbstract:Receptor-mediated cholesterol uptake has been suggested to play a role in maintaining the Adrenal intracellular free cholesterol pool and the ability to produce hormones. Therefore, in the current study, we evaluated the importance of scavenger receptor class B type I (SR-BI)-mediated cholesteryl ester uptake from HDL for Adrenal Glucocorticoid hormone synthesis in vivo. No difference was observed in the plasma level of corticosterone between SR-BI-deficient and wild-type mice under ad libitum feeding conditions. Overnight fasting (∼16 h) stimulated the plasma level of corticosterone by 2-fold in wild-type mice. In contrast, no effect of fasting on plasma corticosterone levels was observed in SR-BI-deficient mice, leading to a 44% lower plasma corticosterone level compared with their wild-type littermate controls. In parallel, an almost complete depletion of lipid stores in the Adrenal cortex of fasted SR-BI-deficient mice was observed. Plasma adrenocorticotropic hormone levels were increased by 5-fold in fasted SR-BI-deficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the Glucocorticoid-responsive genes cholesterol 7α-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-α, which coincided with a 42% decreased plasma glucose level under fasting conditions. In conclusion, we show that the absence of Adrenal HDL cholesteryl ester uptake in SR-BI-deficient mice impairs the Adrenal Glucocorticoid-mediated stress response to fasting as a result of Adrenal Glucocorticoid insufficiency and attenuated liver Glucocorticoid receptor signaling, leading to hypoglycemia under fasting conditions.
Hiroko Fujii - One of the best experts on this subject based on the ideXlab platform.
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Marked Cortisol Production by Intracrine ACTH in GIP- Treated Cultured Adrenal Cells in Which the GIP Receptor Was Exogenously Introduced
2016Co-Authors: Hiroko Fujii, Kousuke Uchida, Takao Susa, Takashi Nakakura, Haruo Hagiwara, Masayoshi Iizuka, Hiroko Okinaga, Mimi Tamamori-adachi, Yuji Tanaka, Tomoki OkazakiAbstract:The ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in the human Adrenal gland causes significant hypercortisolemia after ingestion of each meal and leads to Cushing’s syndrome, implying that human GIPR activation is capable of robustly activating Adrenal Glucocorticoid secretion. In this study, we transiently transfected the human GIPR expression vector into cultured human adrenocortical carcinoma cells (H295R) and treated them with GIP to examine the direct link between GIPR activation and steroidogenesis. Using quantitative RT-PCR assay, we examined gene expression of steroidogenic related proteins, and carried out immunofluorescence analysis to prove that forced GIPR overexpression directly promotes production of steroidogenic enzymes CYP17A1 and CYP21A2 at the single cell level. Immunofluorescence showed that the transfection efficiency of the GIPR gene in H295R cells was approximately 5%, and GIP stimulation enhanced CYP21A2 and CYP17A1 expression in GIPR-introduced H295R cells (H295R-GIPR). Interestingly, these steroidogenic enzymes were also expressed in the GIPR (–) cells adjacent to the GIPR (+) cells. The mRNA levels of a cholesterol transport protein required for all steroidogenesis, StAR, and steroidogenic enzymes, HSD3b2, CYP11A1, CYP21A2, and CYP17A1 increased 1.2-2.1-fold in GIP-stimulated H295R-GIPR cells. These changes were reflected in the culture medium in which 1.5-fold increase in the cortisol concentration was confirmed. Furthermore, the levels of adenocorticotropic hormone (ACTH) receptor and ACTH precursor proopiomelanocortin (POMC) mRNA were upregulate
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marked cortisol production by intracrine acth in gip treated cultured Adrenal cells in which the gip receptor was exogenously introduced
PLOS ONE, 2014Co-Authors: Hiroko Fujii, Mimi Tamamoriadachi, Kousuke Uchida, Takao Susa, Takashi Nakakura, Haruo Hagiwara, Masayoshi Iizuka, Hiroko OkinagaAbstract:The ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in the human Adrenal gland causes significant hypercortisolemia after ingestion of each meal and leads to Cushing’s syndrome, implying that human GIPR activation is capable of robustly activating Adrenal Glucocorticoid secretion. In this study, we transiently transfected the human GIPR expression vector into cultured human adrenocortical carcinoma cells (H295R) and treated them with GIP to examine the direct link between GIPR activation and steroidogenesis. Using quantitative RT-PCR assay, we examined gene expression of steroidogenic related proteins, and carried out immunofluorescence analysis to prove that forced GIPR overexpression directly promotes production of steroidogenic enzymes CYP17A1 and CYP21A2 at the single cell level. Immunofluorescence showed that the transfection efficiency of the GIPR gene in H295R cells was approximately 5%, and GIP stimulation enhanced CYP21A2 and CYP17A1 expression in GIPR-introduced H295R cells (H295R-GIPR). Interestingly, these steroidogenic enzymes were also expressed in the GIPR (–) cells adjacent to the GIPR (+) cells. The mRNA levels of a cholesterol transport protein required for all steroidogenesis, StAR, and steroidogenic enzymes, HSD3β2, CYP11A1, CYP21A2, and CYP17A1 increased 1.2-2.1-fold in GIP-stimulated H295R-GIPR cells. These changes were reflected in the culture medium in which 1.5-fold increase in the cortisol concentration was confirmed. Furthermore, the levels of adenocorticotropic hormone (ACTH) receptor and ACTH precursor proopiomelanocortin (POMC) mRNA were upregulated 2- and 1.5-fold, respectively. Immunofluorescence showed that ACTH expression was detected in GIP-stimulated H295R-GIPR cells. An ACTH-receptor antagonist significantly inhibited steroidogenic gene expression and cortisol production. Immunostaining for both CYP17A1 and CYP21A2 was attenuated in cells treated with ACTH receptor antagonists as well as with POMC siRNA. These results demonstrated that GIPR activation promoted production and release of ACTH, and that steroidogenesis is activated by endogenously secreted ACTH following GIP administration, at least in part, in H295R cells.