Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis.

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.

Analysis of the Reversible Impact of the Chemodrug Busulfan on Mouse Testes.

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.

New perspectives on PPAR, VDR and FXRα as new actors in testicular pathophysiology.

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).

FXRα modulates leydig cell endocrine function in mouse.

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.

Fxralpha gene is a target gene of hCG signaling pathway and represses hCG induced steroidogenesis.

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).

Farnesoid X receptor alpha (FXRα) is a critical actor of the development and pathologies of the male reproductive system.

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.

Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases.

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.

Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways.

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.

Crosstalk between BPA and FXRα Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders.

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.

Cholesterol: A Gatekeeper of Male Fertility?

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.

The Bile Acid Nuclear Receptor FXRα Is a Critical Regulator of Mouse Germ Cell Fate.

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.

Bile acids and male fertility: From mouse to human?

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).

Bile acid homeostasis controls CAR signaling pathways in mouse testis through FXRalpha.

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.

Bile acids and their receptors.

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.

Bile acid-FXRα pathways regulate male sexual maturation in mice.

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).

Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context.

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.

Identification of the link between the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice.

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.

Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology.

Liver X receptors LXRα (NR1H3) and LXRβ (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.

Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice.

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.

LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly.

Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response.

Epigenetic: a molecular link between testicular cancer and environmental exposures.

In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations.

Bile acids: from digestion to cancers.

Bile acids (BAs) are cholesterol metabolites that have been extensively studied these last decades. BAs have been classified in two groups. Primary BAs are synthesized in liver, when secondary BAs are produced by intestinal bacteria.

Emerging roles for LXRs and LRH-1 in female reproduction.

Nutritional status is known to control female reproductive physiology. Many reproductive pathologies such as anorexia nervosa, dystocia and preeclampsia, have been linked to body mass index and to metabolic syndrome. Lipid metabolism has also been associated with ovarian, uterine and placental functions.

Liver X receptors, lipids and their reproductive secrets in the male.

Liver X receptor (LXR) α and LXRβ 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.