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

  • Manon Garcia
  • Laura Thirouard
  • Mélusine Monrose
  • Hélène Holota
  • Angélique De Haze
  • Françoise Caira
  • Claude BeaudoinEmail author
  • David H. VolleEmail author
Review
  • 47 Downloads

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.

Keywords

Bile acid signaling Fertility Cancer 

Notes

Funding

The study was funded by Inserm, CNRS, Université Clermont Auvergne, Région Auvergne (#R12087CC to DHV), Plan cancer (C14012CS), Ligue contre le cancer (comité Puy de Dôme), ARC (R16142CC). Volle’s team received support from the French government IDEX-ISITE initiative 16-IDEX-0001 (CAP 20-25).

Compliance with ethical standards

Conflict of interest

The authors declare to have no conflict of interests.

References

  1. 1.
    Garcia M, Thirouard L, Sedès L et al (2018) Nuclear receptor metabolism of bile acids and xenobiotics: a coordinated detoxification system with impact on health and diseases. Int J Mol Sci.  https://doi.org/10.3390/ijms19113630 Google Scholar
  2. 2.
    Baptissart M, Vega A, Martinot E et al (2013) Farnesoid X receptor alpha: a molecular link between bile acids and steroid signaling? Cell Mol Life Sci CMLS 70:4511–4526.  https://doi.org/10.1007/s00018-013-1387-0 CrossRefGoogle Scholar
  3. 3.
    Baptissart M, Vega A, Maqdasy S et al (2012) Bile acids: from digestion to cancers. Biochimie.  https://doi.org/10.1016/j.biochi.2012.06.022 Google Scholar
  4. 4.
    Carter BA, Taylor OA, Prendergast DR et al (2007) Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res 62:301–306.  https://doi.org/10.1203/PDR.0b013e3181256492 CrossRefGoogle Scholar
  5. 5.
    Owsley E, Chiang JYL (2003) Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene. Biochem Biophys Res Commun 304:191–195CrossRefGoogle Scholar
  6. 6.
    Ricketts M-L, Boekschoten MV, Kreeft AJ et al (2007) The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. Mol Endocrinol 21:1603–1616.  https://doi.org/10.1210/me.2007-0133 CrossRefGoogle Scholar
  7. 7.
    Everson GT (1987) Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. J Lipid Res 28:238–252Google Scholar
  8. 8.
    Houten SM, Volle DH, Cummins CL et al (2007) In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol 21:1312–1323.  https://doi.org/10.1210/me.2007-0113 CrossRefGoogle Scholar
  9. 9.
    Maloney PR, Parks DJ, Haffner CD et al (2000) Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43:2971–2974CrossRefGoogle Scholar
  10. 10.
    Teodoro JS, Rolo AP, Palmeira CM (2011) Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab 22:458–466.  https://doi.org/10.1016/j.tem.2011.07.002 CrossRefGoogle Scholar
  11. 11.
    Wang H, He Q, Wang G et al (2018) FXR modulators for enterohepatic and metabolic diseases. Expert Opin Ther Pat 28:765–782.  https://doi.org/10.1080/13543776.2018.1527906 CrossRefGoogle Scholar
  12. 12.
    Kim I, Morimura K, Shah Y et al (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28:940–946.  https://doi.org/10.1093/carcin/bgl249 CrossRefGoogle Scholar
  13. 13.
    Yang F, Huang X, Yi T et al (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863–867.  https://doi.org/10.1158/0008-5472.CAN-06-1078 CrossRefGoogle Scholar
  14. 14.
    Van Mil SWC, Milona A, Dixon PH et al (2007) Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 133:507–516.  https://doi.org/10.1053/j.gastro.2007.05.015 CrossRefGoogle Scholar
  15. 15.
    Gomez-Ospina N, Potter CJ, Xiao R et al (2016) Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 7:10713.  https://doi.org/10.1038/ncomms10713 CrossRefGoogle Scholar
  16. 16.
    Sèdes L, Martinot E, Baptissart M et al (2017) Bile acids and male fertility: from mouse to human? Mol Aspects Med.  https://doi.org/10.1016/j.mam.2017.05.004 Google Scholar
  17. 17.
    Durazzo M, Premoli A, Di Bisceglie C et al (2006) Alterations of seminal and hormonal parameters: an extrahepatic manifestation of HCV infection? World J Gastroenterol 12:3073–3076CrossRefGoogle Scholar
  18. 18.
    Mooradian AD, Shamma’a M, Salti I, Cortas N (1985) Hypophyseal-gonadal dysfunction in men with non-alcoholic liver cirrhosis. Andrologia 17:72–79CrossRefGoogle Scholar
  19. 19.
    Burra P (2013) Liver abnormalities and endocrine diseases. Best Pract Res Clin Gastroenterol 27:553–563.  https://doi.org/10.1016/j.bpg.2013.06.014 CrossRefGoogle Scholar
  20. 20.
    Karagiannis A, Harsoulis F (2005) Gonadal dysfunction in systemic diseases. Eur J Endocrinol 152:501–513.  https://doi.org/10.1530/eje.1.01886 CrossRefGoogle Scholar
  21. 21.
    Völzke H, Aumann N, Krebs A et al (2010) Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels in men. Int J Androl 33:45–53.  https://doi.org/10.1111/j.1365-2605.2009.00953.x CrossRefGoogle Scholar
  22. 22.
    Baptissart M, Vega A, Martinot E et al (2014) Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice. Hepatology 60:1054–1065.  https://doi.org/10.1002/hep.27204 CrossRefGoogle Scholar
  23. 23.
    Martinot E, Baptissart M, Vega A et al (2017) Bile acid homeostasis controls CAR signaling pathways in mouse testis through FXRalpha. Sci Rep 7:42182.  https://doi.org/10.1038/srep42182 CrossRefGoogle Scholar
  24. 24.
    Muczynski V, Lecureuil C, Messiaen S et al (2012) Cellular and molecular effect of MEHP involving LXRα in human fetal testis and ovary. PLoS One 7:e48266.  https://doi.org/10.1371/journal.pone.0048266 CrossRefGoogle Scholar
  25. 25.
    Maqdasy S, Baptissart M, Vega A et al (2012) Cholesterol and male fertility: what about orphans and adopted? Mol Cell Endocrinol.  https://doi.org/10.1016/j.mce.2012.06.011 Google Scholar
  26. 26.
    Volle DH, Duggavathi R, Magnier BC et al (2007) The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice. Genes Dev 21:303–315.  https://doi.org/10.1101/gad.409307 CrossRefGoogle Scholar
  27. 27.
    Baptissart M, Martinot E, Vega A et al (2016) Bile acid-FXRα pathways regulate male sexual maturation in mice. Oncotarget.  https://doi.org/10.18632/oncotarget.7153 Google Scholar
  28. 28.
    Martinot E, Sèdes L, Baptissart M et al (2017) The bile acid nuclear receptor FXRα is a critical regulator of mouse germ cell fate. Stem Cell Rep 9:315–328.  https://doi.org/10.1016/j.stemcr.2017.05.036 CrossRefGoogle Scholar
  29. 29.
    Alfaro JM, Ricote M, Lobo MVT et al (2002) Immunohistochemical detection of the retinoid acid receptors (RXR-alpha, -beta, -gamma) and Farnesoid X-activated receptor (FXR) in the marbled newt along the annual cycle. Mol Reprod Dev 62:216–222.  https://doi.org/10.1002/mrd.10104 CrossRefGoogle Scholar
  30. 30.
    Bakke M, Zhao L, Hanley NA, Parker KL (2001) SF-1: a critical mediator of steroidogenesis. Mol Cell Endocrinol 171:5–7CrossRefGoogle Scholar
  31. 31.
    Fayard E, Auwerx J, Schoonjans K (2004) LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends Cell Biol 14:250–260.  https://doi.org/10.1016/j.tcb.2004.03.008 CrossRefGoogle Scholar
  32. 32.
    Van Thiel DH, Gavaler JS, Zajko AB, Cobb CF (1985) Consequences of complete bile-duct ligation on the pubertal process in the male rat. J Pediatr Gastroenterol Nutr 4:616–621CrossRefGoogle Scholar
  33. 33.
    Vega A, Martinot E, Baptissart M, De Haze A, Saru JP, Baron S, Caira F, Schoonjans K, Lobaccaro JM, Volle DH (2014) Identification of the linkbetween the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice. Endocrinology 156(2):660–669.  https://doi.org/10.1210/en.2014-1418 CrossRefGoogle Scholar
  34. 34.
    Ahn SW, Gang G-T, Kim YD et al (2013) Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. J Biol Chem 288:15937–15946.  https://doi.org/10.1074/jbc.M113.451773 CrossRefGoogle Scholar
  35. 35.
    Gray MA, Squires EJ (2013) Effects of nuclear receptor transactivation on steroid hormone synthesis and gene expression in porcine Leydig cells. J Steroid Biochem Mol Biol 133:93–100.  https://doi.org/10.1016/j.jsbmb.2012.09.014 CrossRefGoogle Scholar
  36. 36.
    Wang S, Lai K, Moy FJ et al (2006) The nuclear hormone receptor farnesoid X receptor (FXR) Is activated by androsterone. Endocrinology 147:4025–4033.  https://doi.org/10.1210/en.2005-1485 CrossRefGoogle Scholar
  37. 37.
    Catalano S, Malivindi R, Giordano C et al (2010) Farnesoid X receptor, through the binding with steroidogenic factor 1-responsive element, inhibits aromatase expression in tumor leydig cells. J Biol Chem 285:5581–5593.  https://doi.org/10.1074/jbc.M109.052670 CrossRefGoogle Scholar
  38. 38.
    Schoeters G, Den Hond E, Dhooge W et al (2008) Endocrine disruptors and abnormalities of pubertal development. Basic Clin Pharmacol Toxicol 102:168–175.  https://doi.org/10.1111/j.1742-7843.2007.00180.x CrossRefGoogle Scholar
  39. 39.
    Achermann JC, Meeks JJ, Jameson JL (2001) Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 185:17–25CrossRefGoogle Scholar
  40. 40.
    Seminara SB, Achermann JC, Genel M et al (1999) X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab 84:4501–4509.  https://doi.org/10.1210/jcem.84.12.6172 Google Scholar
  41. 41.
    Tabarin A, Achermann JC, Recan D et al (2000) A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism. J Clin Invest 105:321–328.  https://doi.org/10.1172/JCI7212 CrossRefGoogle Scholar
  42. 42.
    Thomas C, Pellicciari R, Pruzanski M et al (2008) Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 7:678–693.  https://doi.org/10.1038/nrd2619 CrossRefGoogle Scholar
  43. 43.
    Manti S, Romano C, Chirico V et al (2014) Nonalcoholic Fatty liver disease/non-alcoholic steatohepatitis in childhood: endocrine-metabolic “mal-programming”. Hepat Mon 14:e17641.  https://doi.org/10.5812/hepatmon.17641 Google Scholar
  44. 44.
    Catalano S, Panza S, Malivindi R et al (2013) Inhibition of Leydig tumor growth by farnesoid X receptor activation: the in vitro and in vivo basis for a novel therapeutic strategy. Int J Cancer 132:2237–2247.  https://doi.org/10.1002/ijc.27915 CrossRefGoogle Scholar
  45. 45.
    Iwamori N, Iwamori T, Matzuk MM (2013) H3K27 demethylase, JMJD3, regulates fragmentation of spermatogonial cysts. PLoS One 8:e72689.  https://doi.org/10.1371/journal.pone.0072689 CrossRefGoogle Scholar
  46. 46.
    Delbès G, Levacher C, Pairault C et al (2004) Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life. Endocrinology 145:3395–3403.  https://doi.org/10.1210/en.2003-1479 CrossRefGoogle Scholar
  47. 47.
    West JA, Viswanathan SR, Yabuuchi A et al (2009) A role for Lin28 in primordial germ-cell development and germ-cell malignancy. Nature 460:909–913.  https://doi.org/10.1038/nature08210 CrossRefGoogle Scholar
  48. 48.
    Sèdes L, Desdoits-Lethimonier C, Rouaisnel B et al (2018) Crosstalk between BPA and FXRα signaling pathways lead to alterations of undifferentiated germ cell homeostasis and male fertility disorders. Stem Cell Rep.  https://doi.org/10.1016/j.stemcr.2018.08.018 Google Scholar
  49. 49.
    Rust C, Wild N, Bernt C et al (2009) Bile acid-induced apoptosis in hepatocytes is caspase-6-dependent. J Biol Chem 284:2908–2916.  https://doi.org/10.1074/jbc.M804585200 CrossRefGoogle Scholar
  50. 50.
    Malivindi R, Santoro M, De Rose D et al (2018) Activated-farnesoid X receptor (FXR) expressed in human sperm alters its fertilising ability. Reprod Camb Engl 156:249–259.  https://doi.org/10.1530/REP-18-0203 Google Scholar
  51. 51.
    Maeda T, Miyata M, Yotsumoto T et al (2004) Regulation of drug transporters by the farnesoid X receptor in mice. Mol Pharm 1:281–289CrossRefGoogle Scholar
  52. 52.
    Casals-Casas C, Desvergne B (2011) Endocrine disruptors: from endocrine to metabolic disruption. Annu Rev Physiol 73:135–162.  https://doi.org/10.1146/annurev-physiol-012110-142200 CrossRefGoogle Scholar
  53. 53.
    Vega A, Baptissart M, Martinot E et al (2014) Hepatotoxicity induced by neonatal exposure to diethylstilbestrol is maintained throughout adulthood via the nuclear receptor SHP. Expert Opin Ther Targets 18:1367–1376.  https://doi.org/10.1517/14728222.2014.964209 Google Scholar
  54. 54.
    Susiarjo M, Xin F, Stefaniak M et al (2017) Bile acids and tryptophan metabolism are novel pathways involved in metabolic abnormalities in BPA-exposed pregnant mice and male offspring. Endocrinology.  https://doi.org/10.1210/en.2017-00046 Google Scholar
  55. 55.
    Hsu C-W, Zhao J, Huang R et al (2014) Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep 4:6437.  https://doi.org/10.1038/srep06437 CrossRefGoogle Scholar
  56. 56.
    Slowinska M, Nynca J, Arnold GJ et al (2017) Proteomic identification of turkey (Meleagris gallopavo) seminal plasma proteins. Poult Sci 96:3422–3435.  https://doi.org/10.3382/ps/pex132 CrossRefGoogle Scholar
  57. 57.
    Liu J, Tong S-J, Wang X, Qu L-X (2014) Farnesoid X receptor inhibits LNcaP cell proliferation via the upregulation of PTEN. Exp Ther Med 8:1209–1212.  https://doi.org/10.3892/etm.2014.1894 CrossRefGoogle Scholar
  58. 58.
    Liu N, Zhao J, Wang J et al (2016) Farnesoid X receptor ligand CDCA suppresses human prostate cancer cells growth by inhibiting lipid metabolism via targeting sterol response element binding protein 1. Am J Transl Res 8:5118–5124Google Scholar
  59. 59.
    Kaeding J, Bouchaert E, Bélanger J et al (2008) Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells. Biochem J 410:245–253.  https://doi.org/10.1042/BJ20071136 CrossRefGoogle Scholar
  60. 60.
    Hammoud AO, Gibson M, Peterson CM et al (2008) Impact of male obesity on infertility: a critical review of the current literature. Fertil Steril 90:897–904.  https://doi.org/10.1016/j.fertnstert.2008.08.026 CrossRefGoogle Scholar
  61. 61.
    Hofny ERM, Ali ME, Abdel-Hafez HZ et al (2010) Semen parameters and hormonal profile in obese fertile and infertile males. Fertil Steril 94:581–584.  https://doi.org/10.1016/j.fertnstert.2009.03.085 CrossRefGoogle Scholar
  62. 62.
    Wiebe JC, Santana A, Medina-Rodríguez N et al (2014) Fertility is reduced in women and in men with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium (T1DGC). Diabetologia 57:2501–2504.  https://doi.org/10.1007/s00125-014-3376-8 CrossRefGoogle Scholar
  63. 63.
    La Vignera S, Condorelli RA, Di Mauro M et al (2015) Reproductive function in male patients with type 1 diabetes mellitus. Andrology 3:1082–1087.  https://doi.org/10.1111/andr.12097 CrossRefGoogle Scholar
  64. 64.
    Agbaje IM, McVicar CM, Schock BC et al (2008) Increased concentrations of the oxidative DNA adduct 7,8-dihydro-8-oxo-2-deoxyguanosine in the germ-line of men with type 1 diabetes. Reprod Biomed Online 16:401–409CrossRefGoogle Scholar
  65. 65.
    Barták V, Josífko M, Horácková M (1975) Juvenile diabetes and human sperm quality. Int J Fertil 20:30–32Google Scholar
  66. 66.
    Morelli A, Comeglio P, Filippi S et al (2012) Testosterone and farnesoid X receptor agonist INT-747 counteract high fat diet-induced bladder alterations in a rabbit model of metabolic syndrome. J Steroid Biochem Mol Biol 132:80–92.  https://doi.org/10.1016/j.jsbmb.2012.02.007 CrossRefGoogle Scholar
  67. 67.
    Maneschi E, Morelli A, Filippi S et al (2012) Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements. J Endocrinol 215:347–362.  https://doi.org/10.1530/JOE-12-0333 CrossRefGoogle Scholar
  68. 68.
    Vega A, Martinot E, Baptissart M et al (2015) Bile acid alters male mouse fertility in metabolic syndrome context. PLoS One 10:e0139946.  https://doi.org/10.1371/journal.pone.0139946 CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Manon Garcia
    • 1
  • Laura Thirouard
    • 1
  • Mélusine Monrose
    • 1
  • Hélène Holota
    • 1
  • Angélique De Haze
    • 1
  • Françoise Caira
    • 1
  • Claude Beaudoin
    • 1
    Email author
  • David H. Volle
    • 1
    Email author
  1. 1.Inserm U1103, Université Clermont Auvergne, CNRS UMR-6293, GReDClermont-FerrandFrance

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