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1
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Zhu W, Cheng X, Zhang H, Li J, Li L, Wei H, Zhang S. Cholic acid inhibits ovarian steroid hormone synthesis and follicular development through farnesoid X receptor signaling in mice. Int J Biol Macromol 2025; 301:140458. [PMID: 39884637 DOI: 10.1016/j.ijbiomac.2025.140458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
This study investigated the effects of cholic acid (CA) on steroid hormone synthesis and follicular development in mouse ovaries and the regulatory mechanism of CA on the expression of steroidogenesis-related genes in granulosa cells. The mice were divided into control and CA groups, and serum and ovarian samples were collected after 1, 2, and 4 months of treatment, respectively. The results showed that CA treatment for 1, 2, and 4 months reduced ovarian weights, disrupted the estrous cycle, decreased the numbers of antral follicles and corpora lutea, and lowered the serum levels of progesterone and estradiol. Moreover, in the ovary, CA treatment upregulated the expression of farnesoid X receptor (FXR) and downregulated the expression of steroidogenesis-related genes, including StAR, CYP11A1, and HSD3B1. Mechanistically, FXR knockdown reversed the inhibitory effects of CA on steroidogenesis-related gene expression and cholesterol uptake in granulosa cells. In vitro follicle culture experiments further confirmed that CA suppressed follicle development, decreased the mRNA expression of steroidogenesis-related genes, and reduced progesterone and estradiol secretion. Collectively, our results demonstrated that CA inhibited follicular development and steroid hormone synthesis through FXR signaling.
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Affiliation(s)
- Wenjun Zhu
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xiaochan Cheng
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Hengyu Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Jiahao Li
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Li Li
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Hengxi Wei
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510642, China
| | - Shouquan Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; National Engineering Research Center for Breeding Swine Industry, Guangdong Provincial Key Laboratory of Agro-Animal Genomics and Molecular Breeding, South China Agricultural University, Guangzhou 510642, China.
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Wang Y, Bendre SV, Krauklis SA, Steelman AJ, Nelson ER. Role of Protein Regulators of Cholesterol Homeostasis in Immune Modulation and Cancer Pathophysiology. Endocrinology 2025; 166:bqaf031. [PMID: 39951497 PMCID: PMC11878532 DOI: 10.1210/endocr/bqaf031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/30/2025] [Accepted: 02/12/2025] [Indexed: 02/16/2025]
Abstract
Cholesterol metabolism and homeostasis have emerged as important factors governing various aspects of cancer biology. Clinical associations between circulating cholesterol and poor prognosis or use of cholesterol-lowering medication and improved prognosis have been noted for several different solid tumors. Mechanistically, cholesterol has many different direct and indirect effects on cancer cells themselves but is also critically involved in shaping the function of other cells of the tumor microenvironment, especially immune cells. There are 2 major feedback loops regulating cholesterol homeostasis. Here we highlight the major proteins involved in the so-called oxysterol-bile acid feedback loop and discuss how each has been implicated in cancer biology. We focus on roles within the immune system with implications for cancer. Given that many of these proteins are enzymes or nuclear receptors, both of which are amenable to small molecule intervention, we posit that this axis may represent a promising area for therapeutic intervention.
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Affiliation(s)
- Yu Wang
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Shruti V Bendre
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Steven A Krauklis
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Andrew J Steelman
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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3
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Garcia M, Holota H, De Haze A, Saru JP, Sanchez P, Battistelli E, Thirouard L, Monrose M, Benoit G, Volle DH, Beaudoin C. Alternative splicing is an FXRα loss-of-function mechanism and impacts energy metabolism in hepatocarcinoma cells. J Biol Chem 2025; 301:108022. [PMID: 39608717 PMCID: PMC11758954 DOI: 10.1016/j.jbc.2024.108022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 11/02/2024] [Accepted: 11/13/2024] [Indexed: 11/30/2024] Open
Abstract
Farnesoid X receptor α (FXRα, NR1H4) is a bile acid-activated nuclear receptor that regulates the expression of glycolytic and lipogenic target genes by interacting with the 9-cis-retinoic acid receptor α (RXRα, NR2B1). Along with cofactors, the FXRα proteins reported thus far in humans and rodents have been observed to regulate both isoform (α1-4)- and tissue-specific gene expression profiles to integrate energy balance and metabolism. Here, we studied the biological functions of an FXRα naturally occurring spliced exon 5 isoform (FXRαse5) lacking the second zinc-binding module of the DNA-binding domain. We demonstrate spliced exon 5 FXRα expression in all FXRα-expressing human and mouse tissues and cells, and that it is unable to bind to its response element or activate FXRα dependent transcription. In parallel, this spliced variant displays differential interaction capacities with its obligate heterodimer partner retinoid X receptor α that may account for silencing of this permissive dimer for signal transduction. Finally, deletion of exon 5 by gene edition in HepG2 cells leads to FXRα loss-of-function, increased expression of LRH1 metabolic sensor and CD36 fatty acid transporter in conjunction with changes in glucose and triglycerides homeostasis. Together, these findings highlight a novel mechanism by which alternative splicing may regulate FXRα gene function to fine-tune adaptive and/or metabolic responses. This finding deepens our understanding on the role of splicing events in hindering FXRα activity to regulate specific transcriptional programs and their contribution in modifying energy metabolism in normal tissues and metabolic diseases.
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Affiliation(s)
- Manon Garcia
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Hélène Holota
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Angélique De Haze
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Jean-Paul Saru
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Phelipe Sanchez
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Edwige Battistelli
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Laura Thirouard
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Mélusine Monrose
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France
| | - Gérard Benoit
- Université de Rennes 1, CNRS UMR6290, INSERM U1305, IGDR, Rennes Cedex, France
| | - David H Volle
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.
| | - Claude Beaudoin
- Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, iGReD Team-Volle, Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.
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Lambrecht R, Delgado ME, Gloe V, Schuetz K, Plazzo AP, Franke B, San Phan T, Fleming J, Mayans O, Brunner T. Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death. Cell Rep 2023; 42:113513. [PMID: 38039134 DOI: 10.1016/j.celrep.2023.113513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 10/09/2023] [Accepted: 11/14/2023] [Indexed: 12/03/2023] Open
Abstract
The nuclear receptor liver receptor homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role in liver cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis and inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen receptor alpha and elevated nuclear factor κB (NF-κB) activity, while LRH-1 overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction of LRH-1's ligand-binding domain and the Rel homology domain of NF-κB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-κB target genes and the proteasomal degradation of pro-apoptotic BCL-2 interacting mediator of cell death prevent mitochondrial apoptosis and ultimately protect mice from TNF-induced liver damage. Collectively, our study emphasizes LRH-1 as a critical, sex-dependent regulator of cell death and inflammation in the healthy and diseased liver.
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Affiliation(s)
- Rebekka Lambrecht
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - M Eugenia Delgado
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Vincent Gloe
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Karina Schuetz
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Anna Pia Plazzo
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Barbara Franke
- Biophysics and Structural Biology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Truong San Phan
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Jennifer Fleming
- Biophysics and Structural Biology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Olga Mayans
- Biophysics and Structural Biology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany
| | - Thomas Brunner
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany.
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5
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Güneş S, Sevim R, Yiğit Z, Çulhacı N, Ünüvar T, Anık A. PUBERTAL VIRILIZATION IN AN ADOLESCENT WITH 46, XY DISORDER OF SEXUAL DEVELOPMENT: A NOVEL MUTATION IN NR5A1 GENE. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2023; 19:364-369. [PMID: 38356974 PMCID: PMC10863962 DOI: 10.4183/aeb.2023.364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Background NR5A1 [Steroidogenic factor 1 (SF1)] is a nuclear receptor that is essential for the development of gonads and adrenal glands as well as the establishment of steroidogenesis in these organs. The clinical findings of the mutations of NR5A1 gene in 46, XY individuals are variable. Virilization at puberty can be seen in some of the 46, XY children who have a female phenotype and are raised as female.A girl aged 13 years and 10 months old was brought by the family for deepening of her voice. On physical examination, her breast development was Tanner stage 2, axillary hair (+) and pubic hair was Tanner stage 4. She had labioscrotal fusion and 4.4 cm phallus (External Masculinisation Score was 6). Hypergonadotropic hypogonadism, low AMH and high testosterone levels were detected in laboratory tests. Uterus was not visualized in pelvic ultrasonography. Karyotype analysis was reported as 46, XY. Sequence analysis of the NR5A1 gene revealed a novel heterozygote c.1075_1089del (p.Leu359_Leu363del) variant. The patient was raised as a female and oestrogen replacement was started following gonadectomy. Conclusion It should be kept in mind that virilization may develop at puberty in individuals with 46, XY disorder of sexual development due to NR5A1 mutation.
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Affiliation(s)
- S. Güneş
- Department of Pediatric Endocrinology, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
| | - R.D. Sevim
- Department of Pediatric Endocrinology, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
| | - Z.M. Yiğit
- Department of Medical Genetics, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
| | - N. Çulhacı
- Department of Medical Pathology, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
| | - T. Ünüvar
- Department of Pediatric Endocrinology, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
| | - A. Anık
- Department of Pediatric Endocrinology, Aydın Adnan Menderes University, Faculty of Medicine, Aydın, Türkiye
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6
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Ahmed A, Reinhold C, Breunig E, Phan TS, Dietrich L, Kostadinova F, Urwyler C, Merk VM, Noti M, Toja da Silva I, Bode K, Nahle F, Plazzo AP, Koerner J, Stuber R, Menche C, Karamitopoulou E, Farin HF, Gollob KJ, Brunner T. Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids. Mol Oncol 2023. [PMID: 36861295 PMCID: PMC10399709 DOI: 10.1002/1878-0261.13414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/28/2023] [Indexed: 03/03/2023] Open
Abstract
Control of tumour development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumours from destruction by the immune system remains currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumour development during an inflammation-induced mouse model of colorectal cancer. We demonstrate that the local synthesis of immunoregulatory glucocorticoids has dual roles in the regulation of intestinal inflammation and tumour development. In the inflammation phase, LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumour development and growth. In established tumours, however, tumour-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumour immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumour organoids into immunocompetent recipient mice resulted in rapid tumour growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumour organoids was characterized by reduced tumour growth and increased immune cell infiltration. In human colorectal tumours, high expression of steroidogenic enzymes correlated with the expression of other immune checkpoints and suppressive cytokines, and negatively correlated with overall patients' survival. Thus, LRH-1-regulated tumour-specific glucocorticoid synthesis contributes to tumour immune escape and represents a novel potential therapeutic target.
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Affiliation(s)
- Asma Ahmed
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany.,Department of Pharmacology, Faculty of Medicine, University of Khartoum, Sudan
| | - Cindy Reinhold
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Eileen Breunig
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Truong San Phan
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Lea Dietrich
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Feodora Kostadinova
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Corinne Urwyler
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Switzerland
| | - Verena M Merk
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Mario Noti
- Institute of Pathology, University of Bern, Switzerland
| | - Israel Toja da Silva
- International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil.,National Institute for Science and Technology - Oncogenomics and Therapeutic Innovation (INCT-INOTE), São Paulo, Brazil
| | - Konstantin Bode
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Fatima Nahle
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Anna Pia Plazzo
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
| | - Julia Koerner
- Division of Immunology, Department of Biology, University of Konstanz, Germany
| | - Regula Stuber
- Institute of Pathology, University of Bern, Switzerland
| | - Constantin Menche
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany
| | | | - Henner F Farin
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany
| | - Kenneth J Gollob
- International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil.,National Institute for Science and Technology - Oncogenomics and Therapeutic Innovation (INCT-INOTE), São Paulo, Brazil.,Albert Einstein Israelite Hospital, São Paulo, Brazil
| | - Thomas Brunner
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Germany
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7
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Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis. Int J Mol Sci 2022; 23:ijms232315398. [PMID: 36499726 PMCID: PMC9738292 DOI: 10.3390/ijms232315398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/25/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Understanding the regulation of the testicular endocrine function leading to testosterone production is a major objective as the alteration of endocrine function is associated with the development of many diseases such as infertility. In the last decades, it has been demonstrated that several endogenous molecules regulate the steroidogenic pathway. Among them, bile acids have recently emerged as local regulators of testicular physiology and particularly endocrine function. Bile acids act through the nuclear receptor FXRα (Farnesoid-X-receptor alpha; NR1H4) and the G-protein-coupled bile acid receptor (GPBAR-1; TGR5). While FXRα has been demonstrated to regulate testosterone synthesis within Leydig cells, no data are available regarding TGR5. Here, we investigated the potential role of TGR5 within Leydig cells using cell culture approaches combined with pharmacological exposure to the TGR5 agonist INT-777. The data show that activation of TGR5 results in a decrease in testosterone levels. TGR5 acts through the PKA pathway to regulate steroidogenesis. In addition, our data show that TGR5 activation leads to an increase in cholesterol ester levels. This suggests that altered lipid homeostasis may be a mechanism explaining the TGR5-induced decrease in testosterone levels. In conclusion, the present work highlights the impact of the TGR5 signaling pathway on testosterone production and reinforces the links between bile acid signaling pathways and the testicular endocrine function. The testicular bile acid pathways need to be further explored to increase our knowledge of pathologies associated with impaired testicular endocrine function, such as fertility disorders.
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8
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Ueda H, Honda A, Miyazaki T, Morishita Y, Hirayama T, Iwamoto J, Nakamoto N, Ikegami T. Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition. PLoS One 2022; 17:e0271308. [PMID: 35819971 PMCID: PMC9275687 DOI: 10.1371/journal.pone.0271308] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022] Open
Abstract
Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.
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Affiliation(s)
- Hajime Ueda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.,Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Takeshi Hirayama
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Junichi Iwamoto
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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9
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Lrh1 can help reprogram sexual cell fate and is required for Sertoli cell development and spermatogenesis in the mouse testis. PLoS Genet 2022; 18:e1010088. [PMID: 35192609 PMCID: PMC8896720 DOI: 10.1371/journal.pgen.1010088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 03/04/2022] [Accepted: 02/09/2022] [Indexed: 01/16/2023] Open
Abstract
The mammalian nuclear hormone receptors LRH1 (NR5A2) and SF1 (NR5A1) are close paralogs that can bind the same DNA motif and play crucial roles in gonadal development and function. Lrh1 is essential for follicle development in the ovary and has been proposed to regulate steroidogenesis in the testis. Lrh1 expression in the testis is highly elevated by loss of the sex regulator Dmrt1, which triggers male-to-female transdifferentiation of Sertoli cells. While Sf1 has a well-defined and crucial role in testis development, no function for Lrh1 in the male gonad has been reported. Here we use conditional genetics to examine Lrh1 requirements both in gonadal cell fate reprogramming and in normal development of the three major cell lineages of the mouse testis. We find that loss of Lrh1 suppresses sexual transdifferentiation, confirming that Lrh1 can act as a key driver in reprogramming sexual cell fate. In otherwise wild-type testes, we find that Lrh1 is dispensable in Leydig cells but is required in Sertoli cells for their proliferation, for seminiferous tubule morphogenesis, for maintenance of the blood-testis barrier, for feedback regulation of androgen production, and for support of spermatogenesis. Expression profiling identified misexpressed genes likely underlying most aspects of the Sertoli cell phenotype. In the germ line we found that Lrh1 is required for maintenance of functional spermatogonia, and hence mutants progressively lose spermatogenesis. Reduced expression of the RNA binding factor Nxf2 likely contributes to the SSC defect. Unexpectedly, however, over time the Lrh1 mutant germ line recovered abundant spermatogenesis and fertility. This finding indicates that severe germ line depletion triggers a response allowing mutant spermatogonia to recover the ability to undergo complete spermatogenesis. Our results demonstrate that Lrh1, like Sf1, is an essential regulator of testis development and function but has a very distinct repertoire of functions.
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10
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de Mattos K, Viger RS, Tremblay JJ. Transcription Factors in the Regulation of Leydig Cell Gene Expression and Function. Front Endocrinol (Lausanne) 2022; 13:881309. [PMID: 35464056 PMCID: PMC9022205 DOI: 10.3389/fendo.2022.881309] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/15/2022] [Indexed: 12/28/2022] Open
Abstract
Cell differentiation and acquisition of specialized functions are inherent steps in events that lead to normal tissue development and function. These processes require accurate temporal, tissue, and cell-specific activation or repression of gene transcription. This is achieved by complex interactions between transcription factors that form a unique combinatorial code in each specialized cell type and in response to different physiological signals. Transcription factors typically act by binding to short, nucleotide-specific DNA sequences located in the promoter region of target genes. In males, Leydig cells play a crucial role in sex differentiation, health, and reproductive function from embryonic life to adulthood. To better understand the molecular mechanisms regulating Leydig cell differentiation and function, several transcription factors important to Leydig cells have been identified, including some previously unknown to this specialized cell type. This mini review summarizes the current knowledge on transcription factors in fetal and adult Leydig cells, describing their roles and mechanisms of action.
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Affiliation(s)
- Karine de Mattos
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Université Laval, Québec City, QC, Canada
| | - Robert S. Viger
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Université Laval, Québec City, QC, Canada
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, QC, Canada
| | - Jacques J. Tremblay
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Université Laval, Québec City, QC, Canada
- Centre de recherche en Reproduction, Développement et Santé Intergénérationnelle, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, QC, Canada
- *Correspondence: Jacques J. Tremblay,
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11
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Pesticides and Male Fertility: A Dangerous Crosstalk. Metabolites 2021; 11:metabo11120799. [PMID: 34940557 PMCID: PMC8707831 DOI: 10.3390/metabo11120799] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/19/2021] [Accepted: 11/19/2021] [Indexed: 12/17/2022] Open
Abstract
In recent decades, an increasing incidence of male infertility has been reported. Interestingly, and considering that pesticides have been used for a long time, the high incidence of this pathological state is concomitant with the increasing use of these chemicals, suggesting they are contributors for the development of human infertility. Data from literature highlight the ability of certain pesticides and/or their metabolites to persist in the environment for long periods of time, as well as to bioaccumulate in the food chain, thus contributing for their chronic exposure. Furthermore, pesticides can act as endocrine disrupting chemicals (EDCs), interfering with the normal function of natural hormones (which are responsible for the regulation of the reproductive system), or even as obesogens, promoting obesity and associated comorbidities, like infertility. Several in vitro and in vivo studies have focused on the effects and possible mechanisms of action of these pesticides on the male reproductive system that cause sundry negative effects, even though through diverse mechanisms, but all may lead to infertility. In this review, we present an up-to-date overview and discussion of the effects, and the metabolic and molecular features of pesticides on somatic cells and germinal tissues that affect germ cell differentiation.
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12
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Qin X, Zhang Y, Lu J, Huang S, Liu Z, Wang X. CYP3A deficiency alters bile acid homeostasis and leads to changes in hepatic susceptibility in rats. Toxicol Appl Pharmacol 2021; 429:115703. [PMID: 34461081 DOI: 10.1016/j.taap.2021.115703] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022]
Abstract
Cytochrome P450 3A (CYP3A) as an important enzyme metabolizes many drugs and a variety of endogenous substances. Bile acids (BA) regulate physiological function by activating BA receptors. In this study, CYP3A1/2 gene knockout (KO) and wild-type (WT) rats were used to investigate the regulatory effects of CYP3A on BA homeostasis and liver function. Compared with WT rats, BA concentrations in serum, liver and small intestine of CYP3A1/2 KO rats increased significantly, which was due to the decrease of catabolism and the increase of synthesis. In particular, the composition of serum BA (overall hydrophobicity) presented an age- and CYP3A-dependent manner. With the aging of WT rats, the serum BA became more hydrophobic, while this trend was delayed in CYP3A1/2 KO rats. Moreover, the level of serum total cholesterol, the precursor of BA synthesis, decreased by about 20% in CYP3A1/2 KO rats, which is due to the low synthesis but high biotransformation rate. The increase of BA pool further led to the change of transcription level of BA receptor in liver (pregnane X receptor) and small intestine (Takeda G-protein receptor 5), and affected the function and morphology of CYP3A1/2 KO rat liver. In conclusion, CYP3A is a key regulator of BA homeostasis in rats, especially in regulating BA pool size, composition and balance of anabolism, and prevents susceptibility to hepatotoxicity under BA overload.
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Affiliation(s)
- Xuan Qin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Center of Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, United States
| | - Yuanjin Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jian Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Shengbo Huang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Zongjun Liu
- Department of Cardiology, Central Hospital of Shanghai Putuo District, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xin Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
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13
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Yan T, Lu H, Sun C, Peng Y, Meng F, Gan R, Cui X, Wu C, Zhang S, Yang Y, Zhang L, Zhang W. Nr5a homologues in the ricefield eel Monopterus albus: Alternative splicing, tissue-specific expression, and differential roles on the activation of cyp19a1a promoter in vitro. Gen Comp Endocrinol 2021; 312:113871. [PMID: 34324842 DOI: 10.1016/j.ygcen.2021.113871] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 11/16/2022]
Abstract
Nr5a (Fushi tarazu factor 1, Ftz-F1) homologues belong to the nuclear receptor superfamily, and are involved in the regulation of reproduction in vertebrates. Four genes encoding Nr5a homologues were present in the genome of ricefield eel, which are designated as nr5a1a, nr5a1b, nr5a2, and nr5a5 in the present study. Alternatively spliced transcripts were identified for nr5a1a and nr5a1b genes. Sequence analysis indicated that nr5a5 is possibly a paralog of nr5a2, and nr5a1b is lost during evolution in some teleosts including tilapia and medaka. Ricefield eel nr5a genes exhibit tissue-specific expression patterns, with nr5a1a and nr5a1b resembling that of the SF-1/Ad4BP (NR5A1) subfamily, and nr5a2 and nr5a5 resembling that of the NR5A2/LRH/FTF subfamily. Transcriptomic analysis revealed parallel expression profiles of nr5a1a, foxl2, and cyp19a1a in ovarian follicles during vitellogenesis, with peak values at the late vitellogenic stage. Real-time PCR indicated that the expression levels of nr5a1a and foxl2 in gonads were decreased significantly during the sexual transition from female to the late intersexual stage. In vitro transient transfection assay showed that Nr5a1a up-regulated ricefield eel cyp19a1a promoter activities synergistically with Foxl2. However, Nr5a1b, Nr5a2, and Nr5a5 could neither activate ricefield eel cyp19a1a promoter alone nor enhance the stimulatory effects of Foxl2 on cyp19a1a promoter activities. Collectively, the above data suggest that Nr5a homologues may have diverse and differential roles in the tissues of ricefield eels. The up-regulation of gonadal nr5a1a and foxl2 during vitellogenesis may be important for the ovarian development whereas their down-regulation during the sexual transition period may be important for the sex change process of ricefield eels, possibly through the regulation of cyp19a1a gene expression.
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Affiliation(s)
- Tao Yan
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Huijie Lu
- Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Chao Sun
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yalian Peng
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Feiyan Meng
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Riping Gan
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Xin Cui
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Chengxiang Wu
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Shen Zhang
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yumei Yang
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Lihong Zhang
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China.
| | - Weimin Zhang
- Institute of Aquatic Economic Animals and Guangdong Province Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, Sun Yat-Sen University, Guangzhou, China.
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14
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Dean AE, Reichardt F, Anakk S. Sex differences feed into nuclear receptor signaling along the digestive tract. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166211. [PMID: 34273530 DOI: 10.1016/j.bbadis.2021.166211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023]
Abstract
Sex differences in physiology are noted in clinical and animal studies. However, mechanisms underlying these observed differences between males and females remain elusive. Nuclear receptors control a wide range of physiological pathways and are expressed in the gastrointestinal tract, including the mouth, stomach, liver and intestine. We investigated the literature pertaining to ER, AR, FXR, and PPAR regulation and highlight the sex differences in nutrient metabolism along the digestive system. We chose these nuclear receptors based on their metabolic functions, and hormonal actions. Intriguingly, we noted an overlap in target genes of ER and FXR that modulate mucosal integrity and GLP-1 secretion, whereas overlap in target genes of PPARα with ER and AR modulate lipid metabolism. Sex differences were seen not only in the basal expression of nuclear receptors, but also in activation as their endogenous ligand concentrations fluctuate depending on nutrient availability. Finally, in this review, we speculate that interactions between the nuclear receptors may influence overall metabolic decisions in the gastrointestinal tract in a sex-specific manner.
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Affiliation(s)
- Angela E Dean
- Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, IL, United States of America
| | - François Reichardt
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America
| | - Sayeepriyadarshini Anakk
- Division of Nutritional Sciences, University of Illinois Urbana Champaign, Urbana, IL, United States of America; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America; Cancer center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
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15
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Mehanovic S, Mendoza-Villarroel RE, Mattos K, Talbot P, Viger RS, Tremblay JJ. Identification of novel genes and pathways regulated by the orphan nuclear receptor COUP-TFII in mouse MA-10 Leydig cells†. Biol Reprod 2021; 105:1283-1306. [PMID: 34225363 DOI: 10.1093/biolre/ioab131] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/31/2021] [Accepted: 07/02/2021] [Indexed: 01/07/2023] Open
Abstract
In males, Leydig cells are the main producers of testosterone and insulin-like 3 (INSL3), two hormones essential for sex differentiation and reproductive functions. Chicken ovalbumin upstream promoter-transcription factors I (COUP-TFI/NR2F1) and COUP-TFII (NR2F2) belong to the steroid/thyroid hormone nuclear receptor superfamily of transcription factors. In the testis, COUP-TFII is expressed and plays a role in the differentiation of cells committed to give rise to fully functional steroidogenic adult Leydig cells. Steroid production has also been shown to be diminished in COUP-TFII-depleted Leydig cells, indicating an important functional role in steroidogenesis. Until now, only a handful of target genes have been identified for COUP-TFII in Leydig cells. To provide new information into the mechanism of action of COUP-TFII in Leydig cells, we performed microarray analyses of COUP-TFII-depleted MA-10 Leydig cells. We identified 262 differentially expressed genes in COUP-TFII-depleted MA-10 cells. Many of the differentially expressed genes are known to be involved in lipid biosynthesis, lipid metabolism, male gonad development, and steroidogenesis. We validated the microarray data for a subset of the modulated genes by RT-qPCR. Downregulated genes included Hsd3b1, Cyp11a1, Prlr, Shp/Nr0b2, Fdx1, Scarb1, Inha and Gsta3. Finally, analysis of the Gsta3 and Inha gene promoters showed that at least two of the downregulated genes are potentially new direct targets for COUP-TFII. These data provide new evidence that further strengthens the important nature of COUP-TFII in steroidogenesis, androgen homeostasis, cellular defense, and differentiation in mouse Leydig cells.
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Affiliation(s)
- Samir Mehanovic
- Recipient of a doctoral studentship from the Fondation du CHU de Québec-Université Laval.,Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2
| | - Raifish E Mendoza-Villarroel
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2
| | - Karine Mattos
- Recipient of a doctoral studentship from the Fondation du CHU de Québec-Université Laval.,Recipient of a doctoral studentship from the Fonds de recherche du Québec-Santé.,Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2
| | - Philippe Talbot
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2
| | - Robert S Viger
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2.,Centre for Research in Reproduction, Development and Intergenerational Health, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, Québec, Canada, G1V 0A6
| | - Jacques J Tremblay
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec-Université Laval, CHUL Room T3-67, Québec City, Québec, Canada, G1V 4G2.,Centre for Research in Reproduction, Development and Intergenerational Health, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, Québec, Canada, G1V 0A6
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16
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Kumar S, Kim HJ, Lee CH, Choi HS, Lee K. Leydig Cell-Specific DAX1-Deleted Mice Has Higher Testosterone Level in the Testis During Pubertal Development. Reprod Sci 2021; 29:955-962. [PMID: 33891289 DOI: 10.1007/s43032-021-00554-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 03/22/2021] [Indexed: 11/28/2022]
Abstract
Testosterone, the male sex hormone, is necessary for the development and function of the male reproductive system. Biosynthesis of testosterone in mammals mainly occurs in testicular Leydig cells. Many proteins such as P450c17, 3β-HSD, and StAR are involved in testicular steroidogenesis. DAX1 is essential for sex development and interacts with nuclear receptors such as steroidogenic factor 1 to inhibit steroidogenesis. In this study, we investigated the role of DAX1 in testicular steroidogenesis in vivo by generating Leydig cell-specific DAX1-knockout mice. Radioimmunoassay revealed that the levels of testosterone and progesterone were higher in Leydig cell-specific DAX1-knockout testes than in the testes from wild-type mice during the first 3-4 weeks of aging. In addition, the expression levels of steroidogenic genes, such as StAR, P450c17, P450scc, and 3β-HSD, were considerably higher in the testes from DAX1-knockout mice. DAX1-deficient mouse testes seemed to attain early puberty with the acceleration of germ cell development. These data suggest that DAX1 regulates the expression of steroidogenic genes, and thereby controls and fine-tunes steroidogenesis during testis development.
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Affiliation(s)
- Sudeep Kumar
- School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Hyo Jeong Kim
- School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
| | - Hueng-Sik Choi
- School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
| | - Keesook Lee
- School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
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17
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Zhou J, Wang Y, Wu D, Wang S, Chen Z, Xiang S, Chan FL. Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer. Oncogene 2021; 40:2625-2634. [PMID: 33750894 PMCID: PMC8049868 DOI: 10.1038/s41388-021-01737-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 01/31/2023]
Abstract
Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2), steroidogenic factor 1 (SF-1, AD4BP, NR5A1) and estrogen-related receptor α (ERRα, NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.
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Affiliation(s)
- Jianfu Zhou
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China ,grid.411866.c0000 0000 8848 7685The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China ,grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yuliang Wang
- grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Dinglan Wu
- grid.488521.2Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Shusheng Wang
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiqiang Chen
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Songtao Xiang
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Franky Leung Chan
- grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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18
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Holota H, Thirouard L, Monrose M, Garcia M, De Haze A, Saru JP, Caira F, Beaudoin C, Volle DH. FXRα modulates leydig cell endocrine function in mouse. Mol Cell Endocrinol 2020; 518:110995. [PMID: 32827571 DOI: 10.1016/j.mce.2020.110995] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/27/2020] [Accepted: 08/14/2020] [Indexed: 01/14/2023]
Abstract
The hypothalamic-pituitary axis exert a major control over endocrine and exocrine testicular functions. The hypothalamic-pituitary axis corresponds to a cascade with the Gonadotropin Releasing Hormone secreted by the hypothalamus, which stimulates the synthesis and the release of Luteinizing Hormone (LH) and Follicle Stimulating Hormone by the gonadotropic cells of the anterior pituitary. The LH signaling pathway controls the steroidogenic activity of the Leydig cells via the activation of the luteinizing hormone/choriogonadotropin receptor. In order to avoid a runaway system, sex steroids exert a negative feedback within hypothalamus and pituitary. Testicular steroidogenesis is locally controlled within Leydig cells. The present work reviews some local regulations of steroidogenesis within the Leydig cells focusing mainly on the roles of the Farnesoid-X-Receptor-alpha and its interactions with several orphan members of the nuclear receptor superfamily. Further studies are required to reinforce our knowledge of the regulation of testicular endocrine function, which is necessary to ensure a better understanding of fertility disorders and then proposed an adequate treatment of the diseases.
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Affiliation(s)
- Hélène Holota
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Laura Thirouard
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Mélusine Monrose
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Manon Garcia
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Angélique De Haze
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Jean-Paul Saru
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Françoise Caira
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - Claude Beaudoin
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - David H Volle
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France.
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19
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Monrose M, Thirouard L, Garcia M, Holota H, De Haze A, Caira F, Beaudoin C, Volle DH. New perspectives on PPAR, VDR and FXRα as new actors in testicular pathophysiology. Mol Aspects Med 2020; 78:100886. [PMID: 32878696 DOI: 10.1016/j.mam.2020.100886] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/21/2022]
Abstract
The incidence of reproductive disorders is constantly increasing and affects 15% of couples, with male's abnormalities diagnosed in almost half of the cases. The male gonads exert two major functions of the testis with the productions of gametes (exocrine function) and of sexual hormones (endocrine function). In the last decades, next to steroid receptors such as estrogen and androgen receptors, the involvement of other members of the nuclear receptor superfamily have been described such as Steroidogenic factor-1 (SF-1), Nerve growth factor IB (NGFIB), Liver-X-Receptorα (LXRα) and Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1). The purpose of this review is to highlight the emerging roles of some members of the nuclear receptor superfamily among which the vitamin-D Receptor (VDR), Peroxisome Proliferator-Activated Receptor (PPAR), Farnesoid-X-Receptor-α (FXRα). We discuss how these receptors could participate to explain male fertility disorders; and their potential to be use as biomarkers or therapeutic targets for management of fertility disorders.
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Affiliation(s)
- M Monrose
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - L Thirouard
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - M Garcia
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - H Holota
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - A De Haze
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - F Caira
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - C Beaudoin
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France
| | - D H Volle
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001, Clermont-Ferrand, France.
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20
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Garcia M, Thirouard L, Monrose M, Holota H, De Haze A, Caira F, Beaudoin C, Volle DH. Farnesoid X receptor alpha (FXRα) is a critical actor of the development and pathologies of the male reproductive system. Cell Mol Life Sci 2019; 76:4849-4859. [PMID: 31407019 PMCID: PMC11105758 DOI: 10.1007/s00018-019-03247-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/19/2019] [Accepted: 07/23/2019] [Indexed: 12/01/2022]
Abstract
The farnesoid-X-receptorα (FXRα; NR1H4) is one of the main bile acid (BA) receptors. During the last decades, through the use of pharmalogical approaches and transgenic mouse models, it has been demonstrated that the nuclear receptor FXRα controls numerous physiological functions such as glucose or energy metabolisms. It is also involved in the etiology or the development of several pathologies. Here, we will review the unexpected roles of FXRα on the male reproductive tract. FXRα has been demonstrated to play functions in the regulation of testicular and prostate homeostasis. Even though additional studies are needed to confirm these findings in humans, the reviewed reports open new field of research to better define the effects of bile acid-FXRα signaling pathways on fertility disorders and cancers.
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Affiliation(s)
- Manon Garcia
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Laura Thirouard
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Mélusine Monrose
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Hélène Holota
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Angélique De Haze
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Françoise Caira
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France
| | - Claude Beaudoin
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France.
| | - David H Volle
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, 28 Place Henri Dunant, 63001, Clermont-Ferrand, France.
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21
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Sproll P, Eid W, Biason-Lauber A. CBX2-dependent transcriptional landscape: implications for human sex development and its defects. Sci Rep 2019; 9:16552. [PMID: 31719618 PMCID: PMC6851130 DOI: 10.1038/s41598-019-53006-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 10/21/2019] [Indexed: 12/27/2022] Open
Abstract
Sex development, a complex and indispensable process in all vertebrates, has still not been completely elucidated, although new genes involved in sex development are constantly being discovered and characterized. Chromobox Homolog 2 (CBX2) is one of these new additions and has been identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD). The mutated CBX2.1 failed to adequately regulate downstream targets important for sex development in humans, specifically steroidogenic factor 1 (NR5A1/SF1). To better place CBX2.1 in the human sex developmental cascade, we performed siRNA and CBX2.1 overexpression experiments and created a complete CRISPR/Cas9-CBX2 knockout in Sertoli-like cells. Furthermore, we deployed Next Generation Sequencing techniques, RNA-Sequencing and DamID-Sequencing, to identify new potential CBX2.1 downstream genes. The combination of these two next generation techniques enabled us to identify genes that are both bound and regulated by CBX2.1. This allowed us not only to expand our current knowledge about the influence of CBX2.1 in human sex development, but also to advance our insight in the mechanisms governing one of the most important decisions during embryonal development, the commitment to either female or male gonads.
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Affiliation(s)
- Patrick Sproll
- Division of Endocrinology, Section of Medicine, University of Fribourg, Fribourg, 1700, Switzerland
| | - Wassim Eid
- Division of Endocrinology, Section of Medicine, University of Fribourg, Fribourg, 1700, Switzerland.,Department of Biochemistry, Medical Research Institute, University of Alexandria, Alexandria, 21526, Egypt
| | - Anna Biason-Lauber
- Division of Endocrinology, Section of Medicine, University of Fribourg, Fribourg, 1700, Switzerland.
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22
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Holota H, Thirouard L, Garcia M, Monrose M, de Haze A, Saru JP, Caira F, Beaudoin C, Volle DH. Fxralpha gene is a target gene of hCG signaling pathway and represses hCG induced steroidogenesis. J Steroid Biochem Mol Biol 2019; 194:105460. [PMID: 31470110 DOI: 10.1016/j.jsbmb.2019.105460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/19/2019] [Accepted: 08/27/2019] [Indexed: 12/14/2022]
Abstract
The bile acid receptor Farnesoid-X-Receptor alpha (FXRα), a member of the nuclear receptor superfamily, is well known for its roles in the enterohepatic tract. In addition, FXRα regulates testicular physiology through the control of both endocrine and exocrine functions. The endocrine function of the Leydig cells is mainly controlled by the hypothalamo-pituitary axis viaLH/chorionic gonadotropin (CG). If FXRα was demonstrated to control the expression of the Lhcgr gene, encoding the LH receptor; the impact of the LH/CG signaling on the Fxrα expression has not been defined so far. Here, we demonstrate that hCG increases the Fxrα gene expression through the protein kinase-A signaling pathway. Fxrα is then involved in a negative feedback of steroid synthesis. These data improve our knowledge of the local control of the testicular steroidogenesis with the identification of the link between the hypothalamo-pituitary axis and the FXRα signaling pathway.
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Affiliation(s)
- Hélène Holota
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Laura Thirouard
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Manon Garcia
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Mélusine Monrose
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Angélique de Haze
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Jean-Paul Saru
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Françoise Caira
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France
| | - Claude Beaudoin
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France.
| | - David H Volle
- Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD, F-63001 Clermont-Ferrand, France.
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23
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Yan YL, Batzel P, Titus T, Sydes J, Desvignes T, BreMiller R, Draper B, Postlethwait JH. A Hormone That Lost Its Receptor: Anti-Müllerian Hormone (AMH) in Zebrafish Gonad Development and Sex Determination. Genetics 2019; 213:529-553. [PMID: 31399485 PMCID: PMC6781894 DOI: 10.1534/genetics.119.302365] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/04/2019] [Indexed: 12/26/2022] Open
Abstract
Fetal mammalian testes secrete Anti-Müllerian hormone (Amh), which inhibits female reproductive tract (Müllerian duct) development. Amh also derives from mature mammalian ovarian follicles, which marks oocyte reserve and characterizes polycystic ovarian syndrome. Zebrafish (Danio rerio) lacks Müllerian ducts and the Amh receptor gene amhr2 but, curiously, retains amh To discover the roles of Amh in the absence of Müllerian ducts and the ancestral receptor gene, we made amh null alleles in zebrafish. Results showed that normal amh prevents female-biased sex ratios. Adult male amh mutants had enormous testes, half of which contained immature oocytes, demonstrating that Amh regulates male germ cell accumulation and inhibits oocyte development or survival. Mutant males formed sperm ducts and some produced a few offspring. Young female mutants laid a few fertile eggs, so they also had functional sex ducts. Older amh mutants accumulated nonvitellogenic follicles in exceedingly large but sterile ovaries, showing that Amh helps control ovarian follicle maturation and proliferation. RNA-sequencing data partitioned juveniles at 21 days postfertilization (dpf) into two groups that each contained mutant and wild-type fish. Group21-1 upregulated ovary genes compared to Group21-2, which were likely developing as males. By 35 dpf, transcriptomes distinguished males from females and, within each sex, mutants from wild types. In adult mutants, ovaries greatly underexpressed granulosa and theca genes, and testes underexpressed Leydig cell genes. These results show that ancestral Amh functions included development of the gonadal soma in ovaries and testes and regulation of gamete proliferation and maturation. A major gap in our understanding is the identity of the gene encoding a zebrafish Amh receptor; we show here that the loss of amhr2 is associated with the breakpoint of a chromosome rearrangement shared among cyprinid fishes.
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Affiliation(s)
- Yi-Lin Yan
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Peter Batzel
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Tom Titus
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Jason Sydes
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Thomas Desvignes
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Ruth BreMiller
- Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403
| | - Bruce Draper
- Department of Molecular and Cellular Biology, University of California, Davis, California 95616
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24
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Sun S, Kelekar S, Kliewer SA, Mangelsdorf DJ. The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation. Genes Dev 2019; 33:1083-1094. [PMID: 31296559 PMCID: PMC6672048 DOI: 10.1101/gad.326868.119] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023]
Abstract
In this study, Sun et al. investigated the role of the orphan nuclear receptor SHP, a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver, in other tissues. They report that SHP functions as a regulator of ER stress in the exocrine pancreas, specifically via the regulation of XBP1s stability. The orphan nuclear receptor SHP (small heterodimer partner) is a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver; however, its function in other tissues is poorly understood. Here, we report an unexpected role for SHP in the exocrine pancreas as a modulator of the endoplasmic reticulum (ER) stress response. SHP expression is induced in acinar cells in response to ER stress and regulates the protein stability of the spliced form of X-box-binding protein 1 (XBP1s), a key mediator of ER stress response. Loss of SHP reduces XBP1s protein level and transcriptional activity, which in turn attenuates the ER stress response during the fasting–feeding cycle. Consequently, SHP-deficient mice also are more susceptible to cerulein-induced pancreatitis. Mechanistically, we show that SHP physically interacts with the transactivation domain of XBP1s, thereby inhibiting the polyubiquitination and degradation of XBP1s by the Cullin3–SPOP (speckle-type POZ protein) E3 ligase complex. Together, our data implicate SHP in governing ER homeostasis and identify a novel posttranslational regulatory mechanism for the key ER stress response effector XBP1.
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Affiliation(s)
- Shengyi Sun
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Sherwin Kelekar
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Steven A Kliewer
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - David J Mangelsdorf
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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25
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Shahoei SH, Kim YC, Cler SJ, Ma L, Anakk S, Kemper JK, Nelson ER. Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages. Endocrinology 2019; 160:1573-1589. [PMID: 31050726 PMCID: PMC6549582 DOI: 10.1210/en.2019-00025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/29/2019] [Indexed: 02/08/2023]
Abstract
The involvement of small heterodimer partner (SHP) in the inhibition of hepatic bile acid synthesis from cholesterol has been established. However, extrahepatic expression of SHP implies that SHP may have regulatory functions other than those in the liver. Here, we find that SHP mRNA expression is high in murine bone marrow cells, suggesting a physiological role within macrophages. Indeed, expression of SHP in macrophages decreases the transcriptional activity and nuclear localization of nuclear factor κB, whereas downregulation of SHP has the opposite effects. Expression of genes associated with macrophage-T cell crosstalk were altered by overexpression or downregulation of SHP. Intriguingly, increasing SHP expression in macrophages resulted in decreased T cell expansion, a hallmark of T cell activation, whereas knockdown of SHP resulted in increased expansion. Analyses of the expanded T cells revealed a dichotomous skewing between effector T cells and regulatory T cells (Tregs), with SHP overexpression reducing Tregs and downregulation of SHP increasing their expansion. The expanded Tregs were confirmed to be suppressive via adoptive transfers. IL-2 and TGF-β, known inducers of Treg differentiation, were found to be regulated by SHP. Furthermore, SHP occupancy at the promoter region of IL-2 was increased after macrophages were challenged with lipopolysaccharide. Neutralizing antibodies to IL-2 and TGF-β inhibited the expansion of Tregs mediated by downregulation of SHP. This study demonstrates that expression and activity of SHP within macrophages can alter T cell fate and identifies SHP as a potential therapeutic target for autoimmune diseases or solid cancers.
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Affiliation(s)
- Sayyed Hamed Shahoei
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Young-Chae Kim
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Samuel J Cler
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Liqian Ma
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Jongsook K Kemper
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, Illinois
- Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois at Urbana-Champaign, Urbana, Illinois
- Correspondence: Erik R. Nelson, PhD, University of Illinois at Urbana-Champaign, 407 South Goodwin Avenue (MC-114), Urbana, Illinois 61801. E-mail:
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26
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Transcriptional Regulation of Ovarian Steroidogenic Genes: Recent Findings Obtained from Stem Cell-Derived Steroidogenic Cells. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8973076. [PMID: 31058195 PMCID: PMC6463655 DOI: 10.1155/2019/8973076] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 10/15/2018] [Accepted: 02/03/2019] [Indexed: 12/16/2022]
Abstract
Ovaries represent one of the primary steroidogenic organs, producing estrogen and progesterone under the regulation of gonadotropins during the estrous cycle. Gonadotropins fluctuate the expression of various steroidogenesis-related genes, such as those encoding steroidogenic enzymes, cholesterol deliverer, and electronic transporter. Steroidogenic factor-1 (SF-1)/adrenal 4-binding protein (Ad4BP)/NR5A1 and liver receptor homolog-1 (LRH-1) play important roles in these phenomena via transcriptional regulation. With the aid of cAMP, SF-1/Ad4BP and LRH-1 can induce the differentiation of stem cells into steroidogenic cells. This model is a useful tool for studying the molecular mechanisms of steroidogenesis. In this article, we will provide insight into the transcriptional regulation of steroidogenesis-related genes in ovaries that are revealed from stem cell-derived steroidogenic cells. Using the cells derived from the model, novel SF-1/Ad4BP- and LRH-1-regulated genes were identified by combined DNA microarray and promoter tiling array analyses. The interaction of SF-1/Ad4BP and LRH-1 with transcriptional regulators in the regulation of ovarian steroidogenesis was also revealed.
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27
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Meinsohn MC, Smith OE, Bertolin K, Murphy BD. The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction. Physiol Rev 2019; 99:1249-1279. [DOI: 10.1152/physrev.00019.2018] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
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Affiliation(s)
- Marie-Charlotte Meinsohn
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Olivia E. Smith
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Kalyne Bertolin
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Bruce D. Murphy
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
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28
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Cariello M, Ducheix S, Maqdasy S, Baron S, Moschetta A, Lobaccaro JMA. LXRs, SHP, and FXR in Prostate Cancer: Enemies or Ménage à Quatre With AR? NUCLEAR RECEPTOR SIGNALING 2018; 15:1550762918801070. [PMID: 30718981 PMCID: PMC6348739 DOI: 10.1177/1550762918801070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 01/03/2018] [Indexed: 12/11/2022]
Abstract
Androgens and androgen receptor (AR, NR3C4) clearly play a crucial role in
prostate cancer progression. Besides, the link between metabolic disorders and
the risk of developing a prostate cancer has been emerging these last years.
Interestingly, “lipid” nuclear receptors such as LXRα/NR1H3 and LXRβ/NR1H2 (as
well as FXRα/NR1H4 and SHP/NR0B2) have been described to decrease the lipid
metabolism, while AR increases it. Moreover, these former orphan nuclear
receptors can regulate androgen levels and modulate AR activity. Thus, it is not
surprising to find such receptors involved in the physiology of prostate. This
review is focused on the roles of liver X receptors (LXRs), farnesoid X receptor
(FXR), and small heterodimeric partner (SHP) in prostate physiology and their
capabilities to interfere with the androgen-regulated pathways by modulating the
levels of active androgen within the prostate. By the use of prostate cancer
cell lines, mice deficient for these nuclear receptors and human tissue
libraries, several authors have pointed out the putative possibility to
pharmacologically target these receptors. These data open a new field of
research for the development of new drugs that could overcome the castration
resistance in prostate cancer, a usual phenomenon in patients.
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Affiliation(s)
| | - Simon Ducheix
- Istituto Nazionale Biostrutture e Biosistemi, Roma, Italy
| | - Salwan Maqdasy
- Université Clermont Auvergne, Clermont-Ferrand, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France.,CHU Clermont-Ferrand, France
| | - Silvère Baron
- Université Clermont Auvergne, Clermont-Ferrand, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
| | - Antonio Moschetta
- "Aldo Moro" University of Bari, Italy.,Istituto Nazionale Biostrutture e Biosistemi, Roma, Italy.,IRCCS Istituto Oncologico "Giovanni Paolo II," Bari, Italy
| | - Jean-Marc A Lobaccaro
- "Aldo Moro" University of Bari, Italy.,Istituto Nazionale Biostrutture e Biosistemi, Roma, Italy.,Université Clermont Auvergne, Clermont-Ferrand, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, Clermont-Ferrand, France
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29
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Sèdes L, Desdoits-Lethimonier C, Rouaisnel B, Holota H, Thirouard L, Lesne L, Damon-Soubeyrand C, Martinot E, Saru JP, Mazaud-Guittot S, Caira F, Beaudoin C, Jégou B, Volle DH. Crosstalk between BPA and FXRα Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders. Stem Cell Reports 2018; 11:944-958. [PMID: 30245210 PMCID: PMC6178796 DOI: 10.1016/j.stemcr.2018.08.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 08/27/2018] [Accepted: 08/27/2018] [Indexed: 12/20/2022] Open
Abstract
Several studies have reported an association between the farnesoid X receptor alpha (FXRα) and estrogenic signaling pathways. Fxrα could thus be involved in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). To test this hypothesis, mice were exposed to BPA and/or stigmasterol (S), an FXRα antagonist. Following the exposure to both molecules, wild-type animals showed impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. The crosstalk between BPA and FXRα is further supported by the lower impact of BPA in mice genetically ablated for Fxrα and the fact that BPA counteracted the effects of FXRα agonists. These effects might result from the downregulation of Fxrα expression following BPA exposure. BPA and S act additively in human testis. Our data demonstrate that FXRα activity modulates the impact of BPA on male gonads and on undifferentiated germ cell population.
BPA and S exposures synergistically induce male fertility disorders BPA regulates Fxr expression BPA and S act additively in human testis
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Affiliation(s)
- Lauriane Sèdes
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Christèle Desdoits-Lethimonier
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Betty Rouaisnel
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Hélène Holota
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Laura Thirouard
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Laurianne Lesne
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Christelle Damon-Soubeyrand
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Emmanuelle Martinot
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Jean-Paul Saru
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Séverine Mazaud-Guittot
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - Françoise Caira
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Claude Beaudoin
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - Bernard Jégou
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
| | - David H Volle
- INSERM U 1103, Université Clermont Auvergne, CNRS, UMR 6293, GReD, Laboratoire Génétique, Reproduction & Développement, 28 Place Henri-Dunant, 63000 Clermont-Ferrand, France.
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Sèdes L, Thirouard L, Maqdasy S, Garcia M, Caira F, Lobaccaro JMA, Beaudoin C, Volle DH. Cholesterol: A Gatekeeper of Male Fertility? Front Endocrinol (Lausanne) 2018; 9:369. [PMID: 30072948 PMCID: PMC6060264 DOI: 10.3389/fendo.2018.00369] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022] Open
Abstract
Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mechanisms implicated through the signaling pathways of some nuclear receptors.
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Baptissart M, Martinot E, Vega A, Sédes L, Rouaisnel B, de Haze A, Baron S, Schoonjans K, Caira F, Volle DH. Bile acid-FXRα pathways regulate male sexual maturation in mice. Oncotarget 2017; 7:19468-82. [PMID: 26848619 PMCID: PMC4991395 DOI: 10.18632/oncotarget.7153] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 01/22/2016] [Indexed: 12/21/2022] Open
Abstract
The bile acid receptor Farnesol-X-Receptor alpha (FRXα) is a member of the nuclear receptor superfamily. FRXα is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. In adult, short term treatment (12 hours) with FRXα agonist inhibits the expression of steroidogenic genes via the induction of the Small heterodimer partner (SHP). However the consequences of FRXα activation on testicular pathophysiology have never been evaluated. We demonstrate here that mice fed a diet supplemented with bile acid during pubertal age show increased incidence of infertility. This is associated with altered differentiation and increase apoptosis of germ cells due to lower testosterone levels. At the molecular level, next to the repression of basal steroidogenesis via the induction expression of Shp and Dax-1, two repressors of steroidogenesis, the main action of the BA-FRXα signaling is through lowering the Leydig cell sensitivity to the hypothalamo-pituitary axis, the main regulator of testicular endocrine function. In conclusion, BA-FRXα signaling is a critical actor during sexual maturation.
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Affiliation(s)
- Marine Baptissart
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Emmanuelle Martinot
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Aurélie Vega
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Lauriane Sédes
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Betty Rouaisnel
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Angélique de Haze
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Silvère Baron
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Françoise Caira
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - David H Volle
- INSERM U 1103, Laboratoire GReD, Campus Universitaire des Cézeaux, TSA 60026, CS 60026, 63178 Aubière Cedex, France.,Université Clermont Auvergne, Université Blaise Pascal, GReD, F-63178 Aubière, France.,CNRS, UMR 6293, GReD, F-63178 Aubière, France.,Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
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Sèdes L, Martinot E, Baptissart M, Baron S, Caira F, Beaudoin C, Volle DH. Bile acids and male fertility: From mouse to human? Mol Aspects Med 2017; 56:101-109. [DOI: 10.1016/j.mam.2017.05.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 05/09/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023]
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Martinot E, Sèdes L, Baptissart M, Holota H, Rouaisnel B, Damon-Soubeyrand C, De Haze A, Saru JP, Thibault-Carpentier C, Keime C, Lobaccaro JMA, Baron S, Benoit G, Caira F, Beaudoin C, Volle DH. The Bile Acid Nuclear Receptor FXRα Is a Critical Regulator of Mouse Germ Cell Fate. Stem Cell Reports 2017; 9:315-328. [PMID: 28669602 PMCID: PMC5511114 DOI: 10.1016/j.stemcr.2017.05.036] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 05/31/2017] [Accepted: 05/31/2017] [Indexed: 12/14/2022] Open
Abstract
Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied. Here, using a phenotyping approach in Fxrα−/− mice, we describe unexpected roles of FXRα on germ cell physiology independent of its effects on somatic cells. FXRα helps establish and maintain an undifferentiated germ cell pool and in turn influences male fertility. FXRα regulates the expression of several pluripotency factors. Among these, in vitro approaches show that FXRα controls the expression of the pluripotency marker Lin28 in the germ cells.
FXRα regulated germ cell apoptotis independently of androgen homeostasis FXRα controls germ cell differentiation FXRα regulates the establishment and maintenance of undifferentiated germ cells In germ cells, FXRα controls the expression of pluripotency markers such as Lin28
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Affiliation(s)
- Emmanuelle Martinot
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Lauriane Sèdes
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Marine Baptissart
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Hélène Holota
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Betty Rouaisnel
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Christelle Damon-Soubeyrand
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Angélique De Haze
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Jean-Paul Saru
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | | | - Céline Keime
- IGBMC - CNRS UMR 7104 - Inserm U 964, 1 BP 10142, 67404 Illkirch Cedex, France
| | - Jean-Marc A Lobaccaro
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Silvère Baron
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France; Centre de Recherche en Nutrition Humaine d'Auvergne, 63000 Clermont-Ferrand, France
| | - Gérard Benoit
- Laboratoire de Biologie Moléculaire de la Cellule, Ecole normale supérieure de Lyon, UMR5239 CNRS/ENS Lyon/UCBL/HCL, 46, allée d'Italie, 69364 Lyon Cedex 07, France
| | - Françoise Caira
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - Claude Beaudoin
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France
| | - David H Volle
- INSERM U 1103, Université Clermont Auvergne, CNRS UMR 6293, Laboratoire GReD, 28 Place Henri Dunant, 63000 Clermont-Ferrand, France.
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Bile acid homeostasis controls CAR signaling pathways in mouse testis through FXRalpha. Sci Rep 2017; 7:42182. [PMID: 28181583 PMCID: PMC5299845 DOI: 10.1038/srep42182] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 01/06/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are molecules with endocrine activities controlling several physiological functions such as immunity, glucose homeostasis, testicular physiology and male fertility. The role of the nuclear BA receptor FXRα in the control of BA homeostasis has been well characterized. The present study shows that testis synthetize BAs. We demonstrate that mice invalidated for the gene encoding FXRα have altered BA homeostasis in both liver and testis. In the absence of FXRα, BA exposure differently alters hepatic and testicular expression of genes involved in BA synthesis. Interestingly, Fxrα-/- males fed a diet supplemented with BAs show alterations of testicular physiology and sperm production. This phenotype was correlated with the altered testicular BA homeostasis and the production of intermediate metabolites of BAs which led to the modulation of CAR signaling pathways within the testis. The role of the CAR signaling pathways within testis was validated using specific CAR agonist (TCPOBOP) and inverse agonist (androstanol) that respectively inhibited or reproduced the phenotype observed in Fxrα-/- males fed BA-diet. These data open interesting perspectives to better define how BA homeostasis contributes to physiological or pathophysiological conditions via the modulation of CAR activity.
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Martinot E, Sèdes L, Baptissart M, Lobaccaro JM, Caira F, Beaudoin C, Volle DH. Bile acids and their receptors. Mol Aspects Med 2017; 56:2-9. [PMID: 28153453 DOI: 10.1016/j.mam.2017.01.006] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/24/2017] [Accepted: 01/24/2017] [Indexed: 02/06/2023]
Abstract
Primary bile acids are synthetized from cholesterol within the liver and then transformed by the bacteria in the intestine to secondary bile acids. In addition to their involvement in digestion and fat solubilization, bile acids also act as signaling molecules. Several receptors are sensors of bile acids. Among these receptors, this review focuses on the nuclear receptor FXRα and the G-protein-coupled receptor TGR5. This review briefly presents the potential links between bile acids and cancers that are discussed in more details in the other articles of this special issue of Molecular Aspects of Medicine focused on "Bile acids, roles in integrative physiology and pathophysiology".
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Affiliation(s)
- Emmanuelle Martinot
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Lauriane Sèdes
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Marine Baptissart
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Jean-Marc Lobaccaro
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Françoise Caira
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - Claude Beaudoin
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France
| | - David H Volle
- INSERM U 1103, Génétique Reproduction et Développement (GReD), F-63170 Aubière, France; Université Clermont Auvergne, GReD, F-63000 Clermont-Ferrand, F-63170 Aubière, France; CNRS, UMR 6293, GReD, F-63170 Aubière, France; Centre de Recherche en Nutrition Humaine d'Auvergne, F-63000 Clermont-Ferrand, France.
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Yazawa T, Imamichi Y, Miyamoto K, Khan MRI, Uwada J, Umezawa A, Taniguchi T. Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]. Endocr J 2016; 63:943-951. [PMID: 27681884 DOI: 10.1507/endocrj.ej16-0373] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Steroid hormones are mainly produced in adrenal glands and gonads. Because steroid hormones play vital roles in various physiological processes, replacement of deficient steroid hormones by hormone replacement therapy (HRT) is necessary for patients with adrenal and gonadal failure. In addition to HRT, tissue regeneration using stem cells is predicted to provide novel therapy. Among various stem cell types, mesenchymal stem cells can be differentiated into steroidogenic cells following ectopic expression of nuclear receptor (NR) 5A subfamily proteins, steroidogenic factor-1 (also known as adrenal 4 binding protein) and liver receptor homolog-1, with the aid of cAMP signaling. Conversely, these approaches cannot be applied to pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, because of poor survival following cytotoxic expression of NR5A subfamily proteins. However, if pluripotent stem cells are first differentiated through mesenchymal lineage, they can also be differentiated into steroidogenic cells via NR5A subfamily protein expression. This approach offers a potential suitable cells for future regenerative medicine and gene therapy for diseases caused by steroidogenesis deficiencies. It represents a powerful tool to investigate the molecular mechanisms involved in steroidogenesis. This article highlights our own and current research on the induction of steroidogenic cells from various stem cells. We also discuss the future direction of their clinical application.
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Affiliation(s)
- Takashi Yazawa
- Department of Biochemistry, Asahikawa Medical University, Asahikawa 078-8510, Japan
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Jin HS, Kim TS, Jo EK. Emerging roles of orphan nuclear receptors in regulation of innate immunity. Arch Pharm Res 2016; 39:1491-1502. [PMID: 27699647 DOI: 10.1007/s12272-016-0841-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 09/23/2016] [Indexed: 01/25/2023]
Abstract
Innate immunity constitutes the first line of defense against pathogenic and dangerous insults. However, it is a double-edged sword, as it functions in both clearance of infection and inflammatory damage. It is therefore important that innate immune responses are tightly controlled to prevent harmful excessive inflammation. Nuclear receptors (NRs) are a family of transcription factors that play critical roles in various physiological responses. Orphan NRs are a subset of NRs for which the ligands and functions are unclear. Accumulating evidence has revealed that orphan NRs play essential roles in innate immune responses to prevent pathogenic inflammatory responses and to enhance antimicrobial host defenses. In this review, we describe current knowledge on the roles and mechanisms of orphan NRs in the regulation of innate immune responses. Discovery of new functions of orphan NRs would facilitate development of novel preventive and therapeutic strategies against human inflammatory diseases.
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Affiliation(s)
- Hyo Sun Jin
- Department of Microbiology, Department of Medical Science, Chungnam National University School of Medicine, 6 Munhwa-dong, Jungku, Daejeon, 301-747, South Korea
| | - Tae Sung Kim
- Department of Microbiology, Department of Medical Science, Chungnam National University School of Medicine, 6 Munhwa-dong, Jungku, Daejeon, 301-747, South Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Department of Medical Science, Chungnam National University School of Medicine, 6 Munhwa-dong, Jungku, Daejeon, 301-747, South Korea.
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Di-Luoffo M, Brousseau C, Tremblay JJ. MEF2 and NR2F2 cooperate to regulate Akr1c14
gene expression in mouse MA-10 Leydig cells. Andrology 2016; 4:335-44. [DOI: 10.1111/andr.12150] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 11/03/2015] [Accepted: 11/19/2015] [Indexed: 01/04/2023]
Affiliation(s)
- M. Di-Luoffo
- Reproduction, Mother and Child Health; Centre de recherche du centre hospitalier universitaire de Québec; Québec City QC Canada
| | - C. Brousseau
- Reproduction, Mother and Child Health; Centre de recherche du centre hospitalier universitaire de Québec; Québec City QC Canada
| | - J. J. Tremblay
- Reproduction, Mother and Child Health; Centre de recherche du centre hospitalier universitaire de Québec; Québec City QC Canada
- Centre de recherche en biologie de la reproduction; Department of Obstetrics, Gynecology and Reproduction; Faculty of Medicine; Université Laval; Québec City QC Canada
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Yazawa T, Imamichi Y, Miyamoto K, Khan MRI, Uwada J, Umezawa A, Taniguchi T. Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1. Zoolog Sci 2015; 32:323-30. [PMID: 26245218 DOI: 10.2108/zs140237] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Steroidogenic factor-1 (SF-1) and liver receptor homolog-1 (LRH-1) belong to the nuclear receptor superfamily and are categorized as orphan receptors. In addition to other nuclear receptors, these play roles in various physiological phenomena by regulating the transcription of target genes. Both factors share very similar structures and exhibit common functions. Of these, the roles of SF-1 and LRH-1 in steroidogenesis are the most important, especially that of SF-1, which was originally discovered and named to reflect such roles. SF-1 and LRH-1 are essential for steroid hormone production in gonads and adrenal glands through the regulation of various steroidogenesis-related genes. As SF-1 is also necessary for the development of gonads and adrenal glands, it is also considered a master regulator of steroidogenesis. Recent studies have clearly demonstrated that LRH-1 also represents another master regulator of steroidogenesis, which similarly to SF-1, can induce differentiation of non-steroidogenic stem cells into steroidogenic cells. Here, we review the functions of both factors in these steroidogenesis-related phenomena.
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Affiliation(s)
- Takashi Yazawa
- 1 Department of Biochemistry, Asahikawa Medical University, Hokkaido 078-8510, Japan
| | - Yoshitaka Imamichi
- 2 Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Kaoru Miyamoto
- 2 Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Md Rafiqul Islam Khan
- 1 Department of Biochemistry, Asahikawa Medical University, Hokkaido 078-8510, Japan
| | - Junsuke Uwada
- 1 Department of Biochemistry, Asahikawa Medical University, Hokkaido 078-8510, Japan
| | - Akihiro Umezawa
- 3 National Research Institute for Child Health and Development, Tokyo 157-8535, Japan
| | - Takanobu Taniguchi
- 1 Department of Biochemistry, Asahikawa Medical University, Hokkaido 078-8510, Japan
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Kim YC, Byun S, Zhang Y, Seok S, Kemper B, Ma J, Kemper JK. Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2. Genome Biol 2015; 16:268. [PMID: 26634251 PMCID: PMC4669652 DOI: 10.1186/s13059-015-0835-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 11/13/2015] [Indexed: 12/15/2022] Open
Abstract
Background Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0835-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Young-Chae Kim
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Sangwon Byun
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Yang Zhang
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Sunmi Seok
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Byron Kemper
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Jian Ma
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. .,Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
| | - Jongsook Kim Kemper
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
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Maqdasy S, El Hajjaji FZ, Baptissart M, Viennois E, Oumeddour A, Brugnon F, Trousson A, Tauveron I, Volle D, Lobaccaro JMA, Baron S. Identification of the Functions of Liver X Receptor-β in Sertoli Cells Using a Targeted Expression-Rescue Model. Endocrinology 2015; 156:4545-57. [PMID: 26402841 DOI: 10.1210/en.2015-1382] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Liver X receptors (LXRs) are key regulators of lipid homeostasis and are involved in multiple testicular functions. The Lxrα(-/-);Lxrβ(-/-) mice have illuminated the roles of both isoforms in maintenance of the epithelium in the seminiferous tubules, spermatogenesis, and T production. The requirement for LXRβ in Sertoli cells have been emphasized by early abnormal cholesteryl ester accumulation in the Lxrβ(-/-) and Lxrα(-/-);Lxrβ(-/-) mice. Other phenotypes, such as germ cell loss and hypogonadism, occur later in life in the Lxrα(-/-);Lxrβ(-/-) mice. Thus, LXRβ expression in Sertoli cells seems to be essential for normal testicular physiology. To decipher the roles of LXRβ within the Sertoli cells, we generated Lxrα(-/-);Lxrβ(-/-):AMH-Lxrβ transgenic mice, which reexpress Lxrβ in Sertoli cells in the context of Lxrα(-/-);Lxrβ(-/-) mice. In addition to lipid homeostasis, LXRβ is necessary for maintaining the blood-testis barrier and the integrity of the germ cell epithelium. LXRβ is also implicated in the paracrine action of Sertoli cells on Leydig cells to modulate T synthesis. The Lxrα(-/-);Lxrβ(-/-) and Lxrα(-/-);Lxrβ(-/-):AMH-Lxrβ mice exhibit lipid accumulation in germ cells after the Abcg8 down-regulation, suggesting an intricate LXRβ-dependent cooperation between the Sertoli cells and germ cells to ensure spermiogenesis. Further analysis revealed also peritubular smooth muscle defects (abnormal lipid accumulation and disorganized smooth muscle actin) and spermatozoa stagnation in the seminiferous tubules. Together the present work elucidates specific roles of LXRβ in Sertoli cell physiology in vivo beyond lipid homeostasis.
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Affiliation(s)
- Salwan Maqdasy
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Fatim-Zohra El Hajjaji
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Marine Baptissart
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Emilie Viennois
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Abdelkader Oumeddour
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Florence Brugnon
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Amalia Trousson
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Igor Tauveron
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - David Volle
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Jean-Marc A Lobaccaro
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
| | - Silvère Baron
- Department of Génétique Reproduction et Développement (GReD) (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Université Blaise Pascal, Centre de Recherche en Nutrition Humaine d'Auvergne (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., D.V., J.-M.A.L., S.B.), and Department of Assistance Médicale à la Procréation (F.B.), CECOS, Centre Hospitalier Universitaire Clermont Ferrand, Centre Hospitalier Universitaire Estaing, F-63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.) and INSERM (S.M., F.-Z.E.H., M.B., A.O., F.B., A.T., I.T., D.V., J.-M.A.L., S.B.), Unité Mixte de Recherche 6293, GReD, F-63177 Aubiere, France; Center for Diagnostics and Therapeutics (E.V.), Georgia State University, Atlanta, Georgia 30302-4010; Veterans Affairs Medical Center (E.V.), Decatur, Georgia 30033; Service d'Endocrinologie, Diabétologie, et Maladies Métaboliques (S.M., I.T.), Hôpital Gabriel Montpied, F-63003 Clermont-Ferrand, France; and Service de Médecine Nucléaire (S.M.), Centre Jean Perrin, F-63011 Clermont-Ferrand, France
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Tremblay JJ. Molecular regulation of steroidogenesis in endocrine Leydig cells. Steroids 2015; 103:3-10. [PMID: 26254606 DOI: 10.1016/j.steroids.2015.08.001] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 07/19/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023]
Abstract
Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. Consequently, the process of steroid hormone biosynthesis is finely regulated. In the testis, the main steroidogenic cells are the Leydig cells. There are two distinct populations of Leydig cells that arise during development: fetal and adult Leydig cells. Fetal Leydig cells are responsible for masculinizing the male urogenital tract and inducing testis descent. These cells atrophy shortly after birth and do not contribute to the adult Leydig cell population. Adult Leydig cells derive from undifferentiated precursors present after birth and become fully steroidogenic at puberty. The differentiation of both Leydig cell populations is controlled by locally produced paracrine factors and by endocrine hormones. In fully differentially and steroidogenically active Leydig cells, androgen production and hormone-responsiveness involve various signaling pathways and downstream transcription factors. This review article focuses on recent developments regarding the origin and function of Leydig cells, the regulation of their differentiation by signaling molecules, hormones, and structural changes, the signaling pathways, kinases, and transcription factors involved in their differentiation and in mediating LH-responsiveness, as well as the fine-tuning mechanisms that ensure adequate production steroid hormones.
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Affiliation(s)
- Jacques J Tremblay
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Québec City, Québec G1V 4G2, Canada; Centre for Research in Biology of Reproduction, Department of Obstetrics, Gynaecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, Québec G1V 0A6, Canada.
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Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context. PLoS One 2015; 10:e0139946. [PMID: 26439743 PMCID: PMC4595338 DOI: 10.1371/journal.pone.0139946] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 09/18/2015] [Indexed: 12/25/2022] Open
Abstract
Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRα and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases.
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Zou A, Lehn S, Magee N, Zhang Y. New Insights into Orphan Nuclear Receptor SHP in Liver Cancer. NUCLEAR RECEPTOR RESEARCH 2015; 2. [PMID: 26504773 PMCID: PMC4618403 DOI: 10.11131/2015/101162] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Small heterodimer partner (SHP; NR0B2) is a unique orphan nuclear receptor (NR) that contains a putative ligand-binding domain but lacks a DNA-binding domain. SHP is a transcriptional corepressor affecting diverse metabolic processes including bile acid synthesis, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology via interaction with multiple NRs and transcriptional factors (TFs). Hepatocellular carcinoma (HCC) is one of the most deadly human cancers worldwide with few therapeutic options and poor prognosis. Recently, it is becoming clear that SHP plays an antitumor role in the development of liver cancer. In this review, we summarize the most recent findings regarding the new SHP interaction partners, new structural insights into SHP’s gene repressing activity, and SHP protein posttranslational modifications by bile acids. We also discuss the pleiotropic role of SHP in regulating cell proliferation, apoptosis, DNA methylation, and inflammation that are related to antitumor role of SHP in HCC. Improving our understanding of SHP’s antitumor role in the development of liver cancer will provide new insights into developing novel treatments or prevention strategies. Future research will focus on developing more efficacious and specific synthetic SHP ligands for pharmaceutical applications in liver cancer and several metabolic diseases such as hypercholesterolemia, obesity, diabetes, and fatty liver disease.
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Affiliation(s)
- An Zou
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sarah Lehn
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Nancy Magee
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Di-Luoffo M, Daems C, Bergeron F, Tremblay JJ. Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells. Biol Reprod 2015; 93:9. [PMID: 26019261 DOI: 10.1095/biolreprod.114.127761] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 05/22/2015] [Indexed: 12/12/2022] Open
Abstract
Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) are transcription factors recently identified in somatic cells of the male gonad. In other tissues, MEF2 factors are essential regulators of organogenesis and cell differentiation. So far in the testis, MEF2 factors were found to regulate Leydig cell steroidogenesis by controlling Nr4a1 and Star gene expression. To expand our understanding of the role of MEF2 in Leydig cells, we performed microarray analyses of MEF2-depleted MA-10 Leydig cells, and the results were analyzed using Partek and Ingenuity Pathway Analysis software. Several genes were differentially expressed in MEF2-depleted Leydig cells, and 16 were validated by quantitative RT-PCR. A large number of these genes are known to be involved in fertility, gonad morphology, and steroidogenesis. These include Ahr, Bmal1, Cyp1b1, Hsd3b1, Hsd17b7, Map2k1, Nr0b2, Pde8a, Por, Smad4, Star, and Tsc22d3, which were all downregulated in the absence of MEF2. In silico analyses revealed the presence of MEF2-binding sites within the first 2 kb upstream of the transcription start site of the Por, Bmal1, and Nr0b2 promoters, suggesting direct regulation by MEF2. Using transient transfections in MA-10 Leydig cells, small interfering RNA knockdown, and a MEF2-Engrailed dominant negative, we found that MEF2 activates the Por, Bmal1, and Nr0b2 promoters and that this requires an intact MEF2 element. Our results identify novel target genes for MEF2 and define MEF2 as an important regulator of Leydig cell function and male reproduction.
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Affiliation(s)
- Mickaël Di-Luoffo
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Québec City, Québec, Canada
| | - Caroline Daems
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Québec City, Québec, Canada
| | - Francis Bergeron
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Québec City, Québec, Canada
| | - Jacques J Tremblay
- Reproduction, Mother and Child Health, Centre de recherche du centre hospitalier universitaire de Québec, Québec City, Québec, Canada Centre de recherche en biologie de la reproduction, Department of Obstetrics, Gynecology, and Reproduction, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
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Pubertal exposure to di-(2-ethylhexyl)-phthalate inhibits G9a-mediated histone methylation during spermatogenesis in mice. Arch Toxicol 2015; 90:955-69. [DOI: 10.1007/s00204-015-1529-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 05/05/2015] [Indexed: 01/30/2023]
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Vega A, Martinot E, Baptissart M, De Haze A, Saru JP, Baron S, Caira F, Schoonjans K, Lobaccaro JMA, Volle DH. Identification of the link between the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice. Endocrinology 2015; 156:660-9. [PMID: 25426871 DOI: 10.1210/en.2014-1418] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The small heterodimer partner (SHP, nuclear receptor subfamily 0, group B, member 2; NR0B2) is an atypical nuclear receptor known mainly for its role in bile acid homeostasis in the enterohepatic tract. We previously showed that NR0B2 controls testicular functions such as testosterone synthesis. Moreover, NR0B2 mediates the deleterious testicular effects of estrogenic endocrine disruptors leading to infertility. The endocrine homeostasis is essential for health, because it controls many physiological functions. This is supported by a large number of studies demonstrating that alterations of steroid activity lead to several kinds of diseases such as obesity and infertility. Within the testis, the functions of the Leydig cells are mainly controlled by the hypothalamo-pituitary axis via LH/chorionic gonadotropin (CG). Here, we show that LH/CG represses Nr0b2 expression through the protein kinase A-AMP protein kinase pathway. Moreover, using a transgenic mouse model invalidated for Nr0b2, we point out that NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by exposure to anti-GnRH compound. Together, our data demonstrate a new link between hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism, making NR0B2 a major actor of testicular physiology in case of alteration of LH/CG levels.
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Affiliation(s)
- Aurélie Vega
- Inserm Unit 1103 (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Génétique Reproduction et Développement (GReD), Boîte Postale 80026; Clermont Université (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Université Blaise Pascal, GReD; and Centre National de la Recherche Scientifique (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), Unité Mixte de recherche 6293, GReD, F-63170 Aubière Cedex, France; Centre de Recherche en Nutrition Humaine d'Auvergne (A.V., E.M., M.B., A.D.H., J.-P.S., S.B., F.C., J.-M.A.L., D.H.V.), F-63000 Clermont-Ferrand Cedex, France; and Institute of Bioengineering (K.S.), Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
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Zheng W, Grafer CM, Kim J, Halvorson LM. Gonadotropin-Releasing Hormone and Gonadal Steroids Regulate Transcription Factor mRNA Expression in Primary Pituitary and Immortalized Gonadotrope Cells. Reprod Sci 2015; 22:285-99. [DOI: 10.1177/1933719114565031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Weiming Zheng
- Core Laboratories, St. Paul University Hospital, Dallas, TX, USA
| | - Constance M. Grafer
- Department of Obstetrics and Gynecology, Green Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Rouiller-Fabre V, Guerquin MJ, N’Tumba-Byn T, Muczynski V, Moison D, Tourpin S, Messiaen S, Habert R, Livera G. Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape. Front Endocrinol (Lausanne) 2015; 6:58. [PMID: 25999913 PMCID: PMC4423451 DOI: 10.3389/fendo.2015.00058] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 04/07/2015] [Indexed: 11/28/2022] Open
Abstract
During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment. Among the chemicals present in the environment (air, water, food, and many consumer products), several can act as endocrine disrupting compounds (EDCs), thus interfering with the endocrine system. Phthalates, bisphenol A (BPA), and diethylstilbestrol (DES) have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development. As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review, we discuss the role of classical nuclear receptors (genomic pathway) in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA, and DES. Among the nuclear receptors, we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR), androgen receptor (AR), estrogen receptors (ERα and β), liver X receptors (LXR), and small heterodimer partner (SHP). First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models) of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s). We also point-out the involvement of other receptors and nuclear receptor-independent pathways.
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Affiliation(s)
- Virginie Rouiller-Fabre
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
- *Correspondence: Virginie Rouiller-Fabre, Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, CEA, DSV, iRCM, SCSR, LDG, BP6, Fontenay aux Roses F-92265, France,
| | - Marie Justine Guerquin
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Thierry N’Tumba-Byn
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Vincent Muczynski
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Delphine Moison
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Sophie Tourpin
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Sébastien Messiaen
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - René Habert
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
| | - Gabriel Livera
- Unit of Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads, Sorbonne Paris Cité, Université Paris Diderot, Fontenay-aux-Roses, France
- CEA, DSV, iRCM, SCSR, LDG, Fontenay-aux-Roses, France
- Unité 967, INSERM, Fontenay aux Roses, France
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Vega A, Baptissart M, Martinot E, Saru JP, Baron S, Schoonjans K, Volle DH. Hepatotoxicity induced by neonatal exposure to diethylstilbestrol is maintained throughout adulthood via the nuclear receptor SHP. Expert Opin Ther Targets 2014; 18:1367-76. [PMID: 25263461 DOI: 10.1517/14728222.2014.964209] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Liver physiology is sensitive to estrogens, which suggests that the liver might be a target of estrogenic endocrine disrupters (EED). However, the long-term consequences of neonatal exposure to EED on liver physiology have rarely been studied. The nuclear receptor small heterodimer partner (SHP) mediates the deleterious effects of neonatal exposure to diethylstilbestrol (DES) on male fertility. OBJECTIVES As SHP is involved in liver homeostasis, we aimed to determine whether neonatal estrogenic exposure also affected adult liver physiology through SHP. Male mouse pups were exposed to DES in the first 5 days of life. RESULTS DES exposure leads to alterations in the postnatal bile acid (BA) synthesis pathway. Neonatal DES-exposure affected adult liver BA metabolism and subsequently triglyceride (TG) homeostasis. The wild-type males neonatally exposed to DES exhibited increased liver weight and altered liver histology in the adult age. The use of deficient male mice revealed that SHP mediates the deleterious effects of DES treatment. These long-term effects of DES were associated with differently timed alterations in the expression of epigenetic factors. CONCLUSIONS However, the molecular mechanisms by which neonatal exposure persist to affect the adult liver physiology remain to be defined. In conclusion, we demonstrate that neonatal DES exposure alters adult hepatic physiology in an SHP-dependent manner.
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Affiliation(s)
- Aurélie Vega
- INSERM U 1103, Génétique Reproduction et Développement (GReD) , BP 80026, F-63171 Aubière Cedex , France +33 4 73407415 ; +33 4 73407042 ;
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