Crosstalk between BPA and FXRα Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders
Lauriane SèdesChristèle LethimonierBetty RouaisnelHélène HolotaLaura ThirouardLaurianne LesnéChristelle Damon‐SoubeyrandEmmanuelle MartinotJean‐Paul SaruSéverine Mazaud‐GuittotFrançoise CairaClaude BeaudoinBernard JégouDavid H. Volle
19
Citation
44
Reference
10
Related Paper
Citation Trend
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.Keywords:
Farnesoid X receptor
Crosstalk
Endocrine disruptor
Farnesoid X receptor
Liver X receptor
Liver receptor homolog-1
Cite
Citations (317)
Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.
Farnesoid X receptor
Pregnane X receptor
Liver X receptor
Retinoid X receptor
Enterohepatic circulation
Cite
Citations (263)
Farnesoid X receptor
Liver X receptor
Dyslipidemia
Cite
Citations (52)
Nuclear receptors (NRs) are ligand-activated transcription factors modulating significant biological functions including cell growth, lipid metabolism, and glucose homeostasis, so they are frequently to be utilized as important drug targets to develop therapeutic reagents. Farnesoid X receptor (FXR) with bile acids as the natural ligands, plays an essential role in regulation of bile acid and glucose metabolism, and is involved in the pathologies of human diseases including diabetes and chronic liver diseases. Thus, FXR is a promising pharmacological target for these diseases. Synthetic FXR agonists like INT-747 developed by Intercept Pharmaceutical Company is in the clinical trial phase III for non-alcoholic steatohepatitis and can be approved as the treatment of primary biliary cirrhosis in 2016. Due to the promising clinical trial results of INT-747, the naturally occurring FXR ligands may be utilized as the preventive nutraceuticals or treatments of the chronic liver diseases and diabetes. In this review, the natural FXR agonists are summarized and their possible interactions with FXR ligand binding region are discussed. Keywords: Farnesoid X receptor (FXR), FXR ligand binding region, liver, NAFLD, nuclear receptors, natural product.
Farnesoid X receptor
Liver X receptor
Small heterodimer partner
Steatohepatitis
Cite
Citations (0)
Farnesoid X receptor
Chenodeoxycholic acid
Liver X receptor
Cite
Citations (61)
AbstractBile acids are end products of cholesterol metabolism. They are exclusively synthesised by the liver and subsequently secreted via the bile duct into the intestine to facilitate the absorption of dietary fat and fat-soluble vitamins. Nuclear receptors are ligand-activated transcription factors. The farnesoid X receptor (FXR) has recently been identified as a bile acid-activated nuclear receptor. FXR controls bile-acid synthesis, conjugation and transport, as well as lipid metabolism. Recent advances in FXR biology demonstrate that FXR may represent a valuable target for the identification of novel drugs to treat dyslipidaemia and cholestasis. However, for therapeutic purposes the development of selective FXR modulators, which only activate or inhibit specific FXR target genes and as such induce specific responses, will be required.Keywordsbile acidcholestasisFXRlipid metabolismnuclear receptor
Farnesoid X receptor
Small heterodimer partner
Cite
Citations (41)
Nuclear receptors function as ligand-inducible transcription factors that regulate various physiological functions such as development, reproduction, and metabolism. Dysregulation of the metabolism of cholesterol, triglyceride, and glucose leads to the metabolic syndrome including type 2 diabetes mellitus, obesity, dyslipidemia, and atherosclerosis. Studies of nuclear receptors promise to provide discoveries of therapeutic agents against the metabolic syndrome. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is activated by bile acids. FXR regulates the metabolism of not only bile acid but also cholesterol, lipoprotein, triglyceride, and glucose, and is considered a potential therapeutic target for the metabolic syndrome because of these functions. Nuclear receptors have two regions for transactivation, a constitutive activation function (AF-1) and a ligand-dependent activation function (AF-2). AF-1 and AF-2 seem to require interactions with coactivators for the activation function and both work synergistically to give full transactivation of nuclear receptors. However, coactivators for AF-1 activity are poorly understood, whereas coactivators required for AF-2 activity have been well studied. To understand the molecular mechanism of AF-1 in FXR, we isolated proteins associated with AF-1 by GST pull-down assay using the N-terminal region of FXR and nuclear extracts from HeLa cells. This review focuses on the roles of FXR and our new findings regarding FXR-associated factors.
Farnesoid X receptor
Liver X receptor
Small heterodimer partner
Pregnane X receptor
Estrogen-related receptor gamma
Cite
Citations (6)
Farnesoid X receptor
Liver X receptor
CYP8B1
Liver receptor homolog-1
Homeostasis
Cite
Citations (89)
The Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors, which plays crucial role in bile acid, cholesterol, lipid and glucose metabolism, as well as in the development of atherosclerosis, intestinal bacterial growth and liver regeneration. FXR is also involved in the pathogenesis of cholestatic diseases, non-alcoholic fatty liver disease and inflammatory bowel disease. Recent evidence further suggests a key role for FXR in apoptosis and cancer. Notably, FXR deficiency promoted intestinal inflammation and tumorigenesis, suggesting that FXR activation might be a promising strategy in the treatment of colon cancer. FXR deficiency in mice led to the development of spontaneous hepatocarcinomas, while FXR inhibition might represent a novel therapeutic approach in Barett's esophagus. In breast cancer cell lines, FXR agonists down-regulated the breast cancer target gene aromatase. FXR inhibited Leydig tumor growth and progression, supporting evidence that FXR may be an important regulator of androgen homoeostasis. Further studies are required in order to establish possible antitumor effects of this nuclear receptor. Either reactivating or inhibiting FXR expression may represent promising therapeutic strategies in the treatment of certain types of human cancer.
Farnesoid X receptor
Cite
Citations (19)
Farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR is highly expressed in liver and intestine and crosstalk mediated by FXR in these two organs is critical in maintaining bile acid homeostasis. FXR deficiency has been implicated in many liver and intestine diseases. However, regulation of transcription by FXR at the genomic level is not known. This study analyzed genome-wide FXR binding in liver and intestine of mice treated with a synthetic FXR ligand (GW4064) by chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq). The results showed a large degree of tissue-specific FXR binding, with only 11% of total sites shared between liver and intestine. The sites were widely distributed between intergenic, upstream, intragenic, and downstream of genes, with novel sites identified within even known FXR target genes. Motif analysis revealed a half nuclear receptor binding site, normally bound by a few orphan nuclear receptors, adjacent to the FXR response elements, indicating possible involvement of some orphan nuclear receptors in modulating FXR function. Furthermore, pathway analysis indicated that FXR may be extensively involved in multiple cellular metabolic pathways. This study reports genome-wide FXR binding in vivo and the results clearly demonstrate tissue-specific FXR/gene interaction. In addition, FXR may be involved in regulating broader biological pathways in maintaining hepatic and intestinal homeostasis.
Farnesoid X receptor
Cite
Citations (192)