RESUMEN
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.
Asunto(s)
Ácidos y Sales Biliares , Células Intersticiales del Testículo , Masculino , Humanos , Células Intersticiales del Testículo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Homeostasis , TestosteronaRESUMEN
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.
Asunto(s)
Genitales Masculinos/crecimiento & desarrollo , Próstata/crecimiento & desarrollo , Receptores Citoplasmáticos y Nucleares/genética , Testículo/crecimiento & desarrollo , Animales , Ácidos y Sales Biliares/metabolismo , Genitales Masculinos/metabolismo , Homeostasis , Humanos , Masculino , Ratones , Próstata/metabolismo , Transducción de Señal/genética , Testículo/metabolismo , Factores de Transcripción/genéticaRESUMEN
Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Enfermedad , Salud , Receptores Citoplasmáticos y Nucleares/metabolismo , Xenobióticos/metabolismo , Animales , Ácidos y Sales Biliares/química , Humanos , Inactivación MetabólicaRESUMEN
LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαß-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.
Asunto(s)
Carcinoma/genética , Colesterol/metabolismo , Neoplasias Experimentales/genética , Receptores Nucleares Huérfanos/genética , Neoplasia Intraepitelial Prostática/genética , Neoplasias de la Próstata/genética , Animales , Carcinoma/metabolismo , Carcinoma/patología , Dieta Alta en Grasa , Regulación hacia Abajo , Proteína Potenciadora del Homólogo Zeste 2 , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Proteínas de Homeodominio/metabolismo , Humanos , Receptores X del Hígado , Masculino , Metilación , Ratones , Ratones Noqueados , Neoplasias Experimentales/patología , Receptores Nucleares Huérfanos/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas de Secreción Prostática/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Liver X receptors LXRα (NR1H3) and LXRß (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERß (NR3A2), and Lxrα/ß. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 µg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/ß; those whose accumulation is repressed by the absence of Lxrα/ß. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/ß. Altogether, our study shows that both nuclear receptors Lxrα and Lxrß are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.
Asunto(s)
Dietilestilbestrol/toxicidad , Receptores Nucleares Huérfanos/genética , Testículo/efectos de los fármacos , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Peso Corporal/efectos de los fármacos , Dietilestilbestrol/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores Nucleares Huérfanos/metabolismo , Células de Sertoli/efectos de los fármacos , Células de Sertoli/patología , Testículo/patologíaRESUMEN
Liver X receptor (LXR) α and LXRß belong to the nuclear receptor superfamily. For many years, they have been called orphan receptors, as no natural ligand was identified. In the last decade, the LXR natural ligands have been shown to be oxysterols, molecules derived from cholesterol. While these nuclear receptors have been abundantly studied for their roles in the regulation of lipid metabolism, it appears that they also present crucial activities in reproductive organs such as testis and epididymis, as well as prostate. Phenotypic analyses of mice lacking LXRs (lxr-/-) pointed out their physiological activities in the various cells and organs regulating reproductive functions. This review summarizes the impact of LXR-deficiency in male reproduction, highlighting the novel information coming from the phenotypic analyses of lxrα-/-, lxrß-/- and lxrα;ß-/- mice. This article is part of a Special Issue entitled: Translating nuclear receptor from health to disease.
Asunto(s)
Lípidos/fisiología , Receptores Nucleares Huérfanos/fisiología , Reproducción , Animales , Epidídimo/anomalías , Humanos , Receptores X del Hígado , Masculino , Ratones , Ratones Noqueados , Receptores Nucleares Huérfanos/genética , Testículo/fisiologíaRESUMEN
Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.
Asunto(s)
Busulfano/farmacología , Fertilidad/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Inmunosupresores/farmacología , Testículo/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , RNA-Seq , Testículo/metabolismoRESUMEN
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.
Asunto(s)
Hormonas Gonadales/metabolismo , Células Intersticiales del Testículo/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Animales , Células Endocrinas/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones , Hipófisis/metabolismo , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Cholesterol is the obligate precursor to adrenal steroids but is cytotoxic at high concentrations. Here, we show the role of the liver X receptors (LXRalpha and LXRbeta) in preventing accumulation of free cholesterol in mouse adrenal glands by controlling expression of genes involved in all aspects of cholesterol utilization, including the steroidogenic acute regulatory protein, StAR, a novel LXR target. Under chronic dietary stress, adrenal glands from Lxralphabeta-/- mice accumulated free cholesterol. In contrast, wild-type animals maintained cholesterol homeostasis through basal expression of genes involved in cholesterol efflux and storage (ABC transporter A1 [ABCA1], apoE, SREBP-1c) while preventing steroidogenic gene (StAR) expression. Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased. Basally, Lxralphabeta-/- mice exhibited a marked decrease in ABCA1 and a derepression of StAR expression, causing a net decrease in cholesterol efflux and an increase in steroidogenesis. These changes occurred under conditions that prevented the acute stress response and resulted in a phenotype more specific to the loss of LXRalpha, including hypercorticosteronemia, cholesterol ester accumulation, and adrenomegaly. These results imply LXRalpha provides a safety valve to limit free cholesterol levels as a basal protective mechanism in the adrenal gland, where cholesterol is under constant flux.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Colesterol/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Glándulas Suprarrenales/citología , Glándulas Suprarrenales/patología , Animales , Células Cultivadas , Corticosterona/sangre , Proteínas de Unión al ADN/genética , Homeostasis , Humanos , Hipertrofia , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tamaño de los Órganos , Compuestos Orgánicos/metabolismo , Receptores Nucleares Huérfanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismoRESUMEN
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.
Asunto(s)
Gonadotropina Coriónica/farmacología , Receptores Citoplasmáticos y Nucleares/genética , Testículo/efectos de los fármacos , Animales , Línea Celular , Masculino , Ratones Endogámicos C57BL , Fosfoproteínas/genética , Progesterona/metabolismo , Receptores de HL/genética , Transducción de Señal/efectos de los fármacos , Testículo/metabolismo , Testosterona/sangre , Testosterona/metabolismoRESUMEN
Liver X receptor-alpha (LXRalpha) and LXRbeta are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have been identified as key players in cholesterol homeostasis and lipid and glucose metabolism as well as immune and inflammatory responses. In the small intestine, LXRs have been shown not only to regulate cholesterol absorption and excretion but also to promote high-density lipoprotein biogenesis via the ATP-binding cassette A1 signaling pathway. Here, using gene expression assays, we identified PPARalpha as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPARalpha mRNA levels in the small intestine but not in the liver. In addition, this specific PPARalpha gene up-regulation occurred in the duodenum, jejunum, and ileum in a dose-dependent manner and translated at the protein level as demonstrated by Western blot analysis. Furthermore, PPARalpha gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPARalpha up-regulation in the small intestine was assessed in PPARalpha-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPARalpha target genes including PDK4 and CPT1. Those effects were completely abolished in PPARalpha-deficient mice, demonstrating the biological relevance of this LXR-PPARalpha transcriptional cascade. Taken together, these results demonstrate that PPARalpha is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Intestinos/fisiología , PPAR alfa/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Benzoatos/farmacología , Bencilaminas/farmacología , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/fisiología , Homeostasis/fisiología , Hidrocarburos Fluorados , Metabolismo de los Lípidos/fisiología , Hígado/fisiología , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Especificidad de Órganos , Receptores Nucleares Huérfanos , PPAR alfa/metabolismo , ARN Mensajero/metabolismo , Receptor Cross-Talk/fisiología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Sulfonamidas/farmacología , Transcripción Genética/fisiología , Activación TranscripcionalRESUMEN
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.
RESUMEN
Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRα) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure.
Asunto(s)
Bilis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Animales , Linaje de la Célula/efectos de los fármacos , Ácido Cólico/farmacología , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Dieta , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Fenotipo , Transducción de Señal/efectos de los fármacos , Espermatozoides/citología , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , ADN Metiltransferasa 3BRESUMEN
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.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Diferenciación Celular , Células Germinativas/patología , Homeostasis , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Fenoles/toxicidad , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal , Adulto , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Feto/efectos de los fármacos , Feto/patología , Células Germinativas/efectos de los fármacos , Células Germinativas/metabolismo , Homeostasis/efectos de los fármacos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Transducción de Señal/efectos de los fármacos , Estigmasterol/toxicidadRESUMEN
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".
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores Acoplados a Proteínas G/genética , Animales , Biotransformación , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiología , Homeostasis/fisiología , Humanos , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Hígado/citología , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Polimorfismo Genético , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de SeñalRESUMEN
Next to their involvement in digestion, bile acids have been defined as signaling molecules. They have been demonstrated to control many physiological functions among which lipid homeostasis, glucose and energy metabolisms. Bile acids are ligands of several receptors and multiple studies using transgenic mouse models defined the major roles of their respective nuclear and membrane receptors namely the Farnesoid-X-Receptor (FXRα) and the G-protein-coupled bile acid receptor 1(GPBAR1; TGR5). Here we review the reports highlighting the impacts of bile acids on testicular physiology and on male reproductive functions. The studies on mouse models open perspectives to better understand the deleterious effects of bile acids on testicular pathophysiologies and fertility disorders. Additional studies are needed to corroborate these correlations in humans.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Acoplados a Proteínas G/genética , Espermatogénesis/efectos de los fármacos , Testículo/metabolismo , Animales , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/farmacología , Metabolismo Energético/genética , Fertilidad/efectos de los fármacos , Fertilidad/genética , Regulación del Desarrollo de la Expresión Génica , Glucosa/metabolismo , Homeostasis , Humanos , Masculino , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Espermatogénesis/genética , Testículo/citología , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo , Testosterona/biosíntesisRESUMEN
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.
Asunto(s)
Ácidos y Sales Biliares/genética , Receptores Citoplasmáticos y Nucleares/genética , Reproducción/genética , Testículo/metabolismo , Androstanoles/farmacología , Animales , Ácidos y Sales Biliares/biosíntesis , Receptor de Androstano Constitutivo , Regulación de la Expresión Génica/efectos de los fármacos , Homeostasis/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Espermatozoides/metabolismoRESUMEN
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.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/metabolismo , Espermatogénesis , Espermatozoides/citología , Envejecimiento , Animales , Células Cultivadas , Femenino , Fertilidad , Eliminación de Gen , Regulación de la Expresión Génica , Células Intersticiales del Testículo/citología , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Reproducción , Células de Sertoli/citología , Células de Sertoli/metabolismo , Espermatozoides/metabolismo , Testículo/citología , Testículo/metabolismo , Testículo/ultraestructuraRESUMEN
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.
Asunto(s)
Ácidos y Sales Biliares/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Maduración Sexual/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Ácidos y Sales Biliares/administración & dosificación , Línea Celular , Ácido Cólico/administración & dosificación , Ácido Cólico/farmacología , Fertilidad/efectos de los fármacos , Isoxazoles/farmacología , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Interferencia de ARN , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Transducción de Señal/genética , Testículo/citología , Testículo/metabolismo , Testosterona/metabolismoRESUMEN
Liver X receptors (LXRs) regulate the expression of a number of genes involved in cholesterol and lipid metabolism after activation by their cognate oxysterol ligands. AKR1-B7 (aldo-keto reductase 1-B7) is expressed in LXR target tissues such as intestine, and because of its known role in detoxifying lipid peroxides, we investigated whether the AKR1-B7 detoxification pathway was regulated by LXRs. Here we show that synthetic LXR agonists increase the accumulation of AKR1-B7 mRNA and protein levels in mouse intestine in wild-type but not lxr(-/-) mice. Regulation of akr1b7 by retinoic X receptor/LXR heterodimers is dependent on three response elements in the proximal murine akr1b7 promoter. Two of these cis-acting elements are specific for regulation by the LXRalpha isoform. In addition, in duodenum of wild-type mice fed a synthetic LXR agonist, we observed an LXR-dependent decrease in lipid peroxidation. Our results demonstrate that akr1b7 is a direct target of LXRs throughout the small intestine, and that LXR activation plays a protective role by decreasing the deleterious effects of lipid peroxides in duodenum. Taken together, these data suggest a new role for LXRs in lipid detoxification.