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Vassilios Papadopoulos - One of the best experts on this subject based on the ideXlab platform.
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ACBD2/ECI2-Mediated Peroxisome-Mitochondria Interactions in Leydig Cell Steroid Biosynthesis
Molecular Endocrinology, 2016Co-Authors: Jinjiang Fan, Leeyah Issop, Martine Culty, Vassilios PapadopoulosAbstract:Fatty acid metabolism and Steroid Biosynthesis are 2 major pathways shared by peroxisomes and mitochondria. Both organelles are in close apposition to the endoplasmic reticulum, with which they communicate via interorganelle membrane contact sites to promote cellular signaling and the exchange of ions and lipids. To date, no convincing evidence of the direct contact between peroxisomes and mitochondria was reported in mammalian cells. Hormone-induced, tightly controlled Steroid hormone Biosynthesis requires interorganelle interactions. Using immunofluorescent staining and live-cell imaging, we found that dibutyryl-cAMP treatment of MA-10 mouse tumor Leydig cells rapidly induces peroxisomes to approach mitochondria and form peroxisome-mitochondrial contact sites/fusion, revealed by the subcellular distribution of the endogenous acyl-coenzyme A-binding domain (ACBD)2/ECI2 isoform A generated by alternative splicing, and further validated using a proximity ligation assay. This event occurs likely via a peroxisome-like structure, which is mediated by peroxisomal and mitochondrial matrix protein import complexes: peroxisomal import receptor peroxisomal biogenesis factor 5 (PEX5), and the mitochondrial import receptor subunit translocase of outer mitochondrial membrane 20 homolog (yeast) protein. Similar results were obtained using the mLTC-1 mouse tumor Leydig cells. Ectopic expression of the ACBD2/ECI2 isoform A in MA-10 cells led to increased basal and hormone-stimulated Steroid formation, indicating that ACBD2/ECI2-mediated peroxisomes-mitochondria interactions favor in the exchange of metabolites and/or macromolecules between these 2 organelles in support of Steroid Biosynthesis. Considering the widespread occurrence of the ACBD2/ECI2 protein, we propose that this protein might serve as a tool to assist in understanding the contact between peroxisomes and mitochondria.
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acbd2 eci2 mediated peroxisome mitochondria interactions in leydig cell Steroid Biosynthesis
Molecular Endocrinology, 2016Co-Authors: Leeyah Issop, Jinjiang Fan, Martine Culty, Vassilios PapadopoulosAbstract:Fatty acid metabolism and Steroid Biosynthesis are 2 major pathways shared by peroxisomes and mitochondria. Both organelles are in close apposition to the endoplasmic reticulum, with which they communicate via interorganelle membrane contact sites to promote cellular signaling and the exchange of ions and lipids. To date, no convincing evidence of the direct contact between peroxisomes and mitochondria was reported in mammalian cells. Hormone-induced, tightly controlled Steroid hormone Biosynthesis requires interorganelle interactions. Using immunofluorescent staining and live-cell imaging, we found that dibutyryl-cAMP treatment of MA-10 mouse tumor Leydig cells rapidly induces peroxisomes to approach mitochondria and form peroxisome-mitochondrial contact sites/fusion, revealed by the subcellular distribution of the endogenous acyl-coenzyme A-binding domain (ACBD)2/ECI2 isoform A generated by alternative splicing, and further validated using a proximity ligation assay. This event occurs likely via a peroxisome-like structure, which is mediated by peroxisomal and mitochondrial matrix protein import complexes: peroxisomal import receptor peroxisomal biogenesis factor 5 (PEX5), and the mitochondrial import receptor subunit translocase of outer mitochondrial membrane 20 homolog (yeast) protein. Similar results were obtained using the mLTC-1 mouse tumor Leydig cells. Ectopic expression of the ACBD2/ECI2 isoform A in MA-10 cells led to increased basal and hormone-stimulated Steroid formation, indicating that ACBD2/ECI2-mediated peroxisomes-mitochondria interactions favor in the exchange of metabolites and/or macromolecules between these 2 organelles in support of Steroid Biosynthesis. Considering the widespread occurrence of the ACBD2/ECI2 protein, we propose that this protein might serve as a tool to assist in understanding the contact between peroxisomes and mitochondria.
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De novo Steroid Biosynthesis in human prostate cell lines and biopsies.
The Prostate, 2016Co-Authors: Monica Sakai, Daniel B. Martinez-arguelles, Armen Aprikian, Anthony M. Magliocco, Vassilios PapadopoulosAbstract:BACKGROUND Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo Steroids, we examined the expression of key enzymes and proteins involved in Steroid Biosynthesis and metabolism. METHODS Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with Steroid Biosynthesis studies in normal and BPH cells. RESULTS Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydroxymethylglutaryl-CoA reductase (HMGCR), the mitochondrial translocator protein TSPO and cholesterol side chain cleavage enzyme CYP11A1 were only observed in WPMY-1, BPH-1, and LNCaP cells. HSD3B1, HSD3B2, and CYP17A1 are involved in androgen formation and were not found in most cell lines. WPE1-NA22 and BPH-1 cells were unable to synthesize de novo Steroids from mevalonate. Moreover, androgen-deprived cells did not have alterations in the expression of enzymes that could lead to de novo Steroid formation. All prostate specimens expressed TSPO and CYP11A1. HSD3B1/2, CYP17A1, HSD17B5, and CYP19A1 mRNA expression was distinct to the profile observed in cells lines. The majority of BPH (90.9%) and PCa (83.1%) specimens contained CYP17A1, compared to control (normal) specimens (46.7%). BPH (82%), PCa (59%), normal (40%), and CRPC (34%) specimens expressed the four key enzymes that metabolize cholesterol to androgens. CONCLUSION These studies question the use of prostate cell lines to study Steroid Biosynthesis and demonstrate that human prostate samples contain transcripts encoding for key Steroidogenic enzymes and proteins indicating that they have the potential to synthesize de novo Steroids. We propose CYP17A1 as a candidate enzyme that can be used for patient stratification and treatment in BPH and PCa. Prostate 76:575–587, 2016. © 2016 Wiley Periodicals, Inc.
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Steroid Biosynthesis in adipose tissue.
Steroids, 2015Co-Authors: Vassilios Papadopoulos, Veera VihmaAbstract:Tissue-specific expression of Steroidogenic enzymes allows the modulation of active Steroid levels in a local manner. Thus, the measurement of local Steroid concentrations, rather than the circulating levels, has been recognized as a more accurate indicator of the Steroid action within a specific tissue. Adipose tissue, one of the largest endocrine tissues in the human body, has been established as an important site for Steroid storage and metabolism. Locally produced Steroids, through the enzymatic conversion from Steroid precursors delivered to adipose tissue, have been proven to either functionally regulate adipose tissue metabolism, or quantitatively contribute to the whole body's Steroid levels. Most recently, it has been suggested that adipose tissue may contain the Steroidogenic machinery necessary for the initiation of Steroid Biosynthesis de novo from cholesterol. This review summarizes the evidence indicating the presence of the entire Steroidogenic apparatus in adipose tissue and discusses the potential roles of local Steroid products in modulating adipose tissue activity and other metabolic parameters.
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Cholesterol Trafficking for Steroid Biosynthesis in MA-10 Mouse Tumor Leydig Cells
The FASEB Journal, 2015Co-Authors: Sathvika Jagannathan, Seimia Chebbi, Françoise Hullin-matsuda, Toshihide Kobayashi, Vassilios PapadopoulosAbstract:The hormone-sensitive and rate-limiting step in Steroid Biosynthesis is the movement of cholesterol from intracellular sources to the inner mitochondrial membrane (IMM). Despite the numerous studie...
Jose Ignacio Gil - One of the best experts on this subject based on the ideXlab platform.
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non targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, Cristina Garciaviguera, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, Jose Miguel Martinezsanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p<0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake.
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Non-targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, C. García-viguera, J. M. Martinez-sanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24 h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p < 0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake. (C) 2012 Elsevier Ltd. All rights reserved.
Douglas M. Stocco - One of the best experts on this subject based on the ideXlab platform.
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Synergistic activation of Steroidogenic acute regulatory protein expression and Steroid Biosynthesis by retinoids: involvement of cAMP/PKA signaling.
Endocrinology, 2014Co-Authors: Pulak R. Manna, Cloyce L. Stetson, Andrzej Slominski, Steven R. King, Douglas M. StoccoAbstract:Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as Steroidogenesis. Regulation of Steroid Biosynthesis is principally mediated by the Steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of Steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and Steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance ...
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synergistic activation of Steroidogenic acute regulatory protein expression and Steroid Biosynthesis by retinoids involvement of camp pka signaling
Endocrinology, 2014Co-Authors: Pulak R. Manna, Cloyce L. Stetson, Andrzej Slominski, Steven R. King, Douglas M. StoccoAbstract:Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the action of retinoids that play important roles in reproductive development and function, as well as Steroidogenesis. Regulation of Steroid Biosynthesis is principally mediated by the Steroidogenic acute regulatory protein (StAR); however, the modes of action of retinoids in the regulation of Steroidogenesis remain obscure. In this study we demonstrate that all-trans retinoic acid (atRA) enhances StAR expression, but not its phosphorylation (P-StAR), and progesterone production in MA-10 mouse Leydig cells. Activation of the protein kinase A (PKA) cascade, by dibutyrl-cAMP or type I/II PKA analogs, markedly increased retinoid-responsive StAR, P-StAR, and Steroid levels. Targeted silencing of endogenous RARα and RXRα, with small interfering RNAs, resulted in decreases in 9-cis RA-stimulated StAR and progesterone levels. Truncation of and mutational alterations in the 5′-flanking region of the StAR gene demonstrated the importance ...
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The role of PBR/TSPO in Steroid Biosynthesis challenged.
Endocrinology, 2014Co-Authors: Douglas M. StoccoAbstract:The events that regulate the rapid synthesis of Steroid hormones in response to trophic hormone stimulation of the Steroidogenic cells have been the ongoing subject of intense interest for several decades. Much of the early work performed in this area determined that the acute regulation of Steroid hormone Biosynthesis required the rapid, de novo synthesis of a protein(s) whose function appeared to be involved in mediating the delivery of cholesterol, the substrate for all Steroid hormones, from the outer mitochondrial membrane to the inner mitochondrial membrane. The existence of a protein that was necessary for intramitochondrial transfer of cholesterol was first postulated by James Ferguson in 1963 (1). This transfer is an absolute requirement for Steroid Biosynthesis, because the cholesterol side-chain cleavage enzyme system that converts cholesterol to pregnenolone, the first Steroid synthesized, resides on the inner side of the inner mitochondrial membrane. As such, the hydrophobic cholesterol substrate is unable to traverse the aqueous intermembrane space and reach the inner mitochondrial membrane through diffusion. The next 3 decades saw a focused interest in determining the identity of this putative regulator protein (2–13). These studies gave rise to a list of the characteristics that the putative protein regulator appeared to possess, including those described above. Later work introduced other putative regulator proteins, the sterol carrier protein 2 (14), the Steroidogenesis activator polypeptide (15, 16), the peripheral benzodiazepine receptor (PBR) (17), and the Steroidogenic acute regulatory protein (StAR) (18). Although space limitations do not allow for a critical evaluation of the characteristics of each of the candidates that have been put forth as the putative regulator protein over the years, these candidates have been described in an earlier review (19).
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the role of pbr tspo in Steroid Biosynthesis challenged
Endocrinology, 2014Co-Authors: Douglas M. StoccoAbstract:The events that regulate the rapid synthesis of Steroid hormones in response to trophic hormone stimulation of the Steroidogenic cells have been the ongoing subject of intense interest for several decades. Much of the early work performed in this area determined that the acute regulation of Steroid hormone Biosynthesis required the rapid, de novo synthesis of a protein(s) whose function appeared to be involved in mediating the delivery of cholesterol, the substrate for all Steroid hormones, from the outer mitochondrial membrane to the inner mitochondrial membrane. The existence of a protein that was necessary for intramitochondrial transfer of cholesterol was first postulated by James Ferguson in 1963 (1). This transfer is an absolute requirement for Steroid Biosynthesis, because the cholesterol side-chain cleavage enzyme system that converts cholesterol to pregnenolone, the first Steroid synthesized, resides on the inner side of the inner mitochondrial membrane. As such, the hydrophobic cholesterol substrate is unable to traverse the aqueous intermembrane space and reach the inner mitochondrial membrane through diffusion. The next 3 decades saw a focused interest in determining the identity of this putative regulator protein (2–13). These studies gave rise to a list of the characteristics that the putative protein regulator appeared to possess, including those described above. Later work introduced other putative regulator proteins, the sterol carrier protein 2 (14), the Steroidogenesis activator polypeptide (15, 16), the peripheral benzodiazepine receptor (PBR) (17), and the Steroidogenic acute regulatory protein (StAR) (18). Although space limitations do not allow for a critical evaluation of the characteristics of each of the candidates that have been put forth as the putative regulator protein over the years, these candidates have been described in an earlier review (19).
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Mechanisms of epidermal growth factor signaling: regulation of Steroid Biosynthesis and the Steroidogenic acute regulatory protein in mouse Leydig tumor cells.
Biology of Reproduction, 2002Co-Authors: Pulak R. Manna, Ilpo Huhtaniemi, Xingjia Wang, Darrell W. Eubank, Douglas M. StoccoAbstract:Abstract Steroid hormone Biosynthesis in the adrenals and gonads is regulated by the Steroidogenic acute regulatory (StAR) protein through its action in mediating the intramitochondrial transport of cholesterol. A role for epidermal growth factor (EGF) in modulating Steroidogenesis has been previously determined, but the mechanism of its action remains unknown. The present investigation was designed to explore the potential mechanism of action of mouse EGF (mEGF) in the regulation of Steroid Biosynthesis and StAR protein expression in mLTC-1 mouse Leydig tumor cells. We show that treatment of mLTC-1 cells with mEGF significantly increased the levels of progesterone (P), StAR protein, and StAR mRNA in a time- and dose-dependent manner. The coordinate induction of P synthesis and StAR gene expression by mEGF was effectively inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. Also, longer exposure of mLTC-1 cells to mEGF produced a marked decrease in LH-receptor mRNA expressio...
M N Horcajada - One of the best experts on this subject based on the ideXlab platform.
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non targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, Cristina Garciaviguera, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, Jose Miguel Martinezsanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p<0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake.
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Non-targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, C. García-viguera, J. M. Martinez-sanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24 h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p < 0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake. (C) 2012 Elsevier Ltd. All rights reserved.
Sonia Medina - One of the best experts on this subject based on the ideXlab platform.
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non targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, Cristina Garciaviguera, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, Jose Miguel Martinezsanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p<0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake.
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Non-targeted metabolomic approach reveals urinary metabolites linked to Steroid Biosynthesis pathway after ingestion of citrus juice
Food Chemistry, 2013Co-Authors: Sonia Medina, Federico Ferreres, M N Horcajada, Jesus Orduna, Maria Saviron, G Zurek, C. García-viguera, J. M. Martinez-sanz, Jose Ignacio GilAbstract:Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24 h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p < 0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the Steroid Biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake. (C) 2012 Elsevier Ltd. All rights reserved.