FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice

Hoekstra, Menno; Sluis, Ronald J. van der; Li, Zhaosha; Oosterveer, Maaike H.; Groen, Albert K.; Berkel, Theo J.C. Van

doi:10.1016/j.mce.2012.05.010

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…Our data reinforce the links between FXRα signaling pathways and steroid metabolism [ 23 , 24 ]. This is of major importance as endocrine homeostasis is a critical physiological process, as alteration could lead to various diseases.…”

Section: Discussionsupporting

confidence: 87%

Bile acid-FXRα pathways regulate male sexual maturation in mice

et al. 2016

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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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Section: Discussionsupporting

confidence: 87%

Bile acid-FXRα pathways regulate male sexual maturation in mice

et al. 2016

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“…FXR belongs to the superfamily of nuclear receptor transcription factors and can be activated by many naturally occurred endogenous bile acids (16). It is abundantly expressed in the tissues with active cholesterol metabolism including the liver, intestine, and adrenal gland, where FXR plays an important role in bile acid biosynthesis and transport, cholesterol metabolism, and glucocorticoid production (17)(18)(19). It has been previously reported that FXR is also highly expressed in the kidney and is critical for maintaining renal function (9).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor is essential for the survival of renal medullary collecting duct cells under hypertonic stress

Huang

Luan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown. In the present study, we demonstrate that 24-hours water restriction selectively up-regulated renal medullary expression of FXR with little MCD apoptosis in wild-type mice. In contrast, water deprivation caused a massive apoptosis of MCDs in both global FXR gene-deficient mice and collecting duct-specific FXR knockout mice. In vitro studies showed that hypertonicity significantly increased FXR and tonicity response enhancer binding protein (TonEBP) expression in mIMCD3 cell line and primary cultured MCDs. Activation and overexpression of FXR markedly increased cell viability and decreased cell apoptosis under hyperosmotic conditions. In addition, FXR can increase gene expression and nuclear translocation of TonEBP. We conclude that FXR protects MCDs from hypertonicity-induced cell injury very likely via increasing TonEBP expression and nuclear translocation. This study provides insights into the molecular mechanism by which FXR enhances urine concentration via maintaining cell viability of MCDs under hyperosmotic condition.

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“…FXR has also been found to be expressed in many "nonclassical" bile salt target tissues, including the vasculature and macrophages, where FXR influences vascular tension and regulates the unloading of cholesterol from foam cells, respectively (34). It has been previously reported that FXR is expressed in the adrenal glands and that its activation by GW4064 modulates adrenal cholesterol metabolism and glucocorticoid synthesis (35). The present study demonstrates that the kidney has constitutively high expression of FXR, with a ubiquitous expression pattern along renal tubules, suggesting that FXR may play an important role in renal physiology and pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.water homeostasis | bile acid receptor T he farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, with the typical functional domains including the DNA binding domain and the ligand binding domain. Upon binding to its ligands, FXR forms a heterodimer with another nuclear receptor, retinoid X receptor, whereupon the receptor dimer binds to the FXR response element (FXRE) located in the promoter regions of FXR target genes, thereby regulating the transcription of these genes (1-3). The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).FXR is highly expressed in the liver and intestine, where it functions as an intracellular sensor of bile acids and is required for the negative feedback regulation of bile acid biosynthesis and its enterohepatic cycle (7,8). Most recently FXR has been found to be involved in the regulation of adrenal and vascular function, as well as hepatic glucose and lipid metabolism, which suggests an important role for FXR in many tissues beyond the hepatointestinal system (9-12). Among most tissues tested, the kidney exhibits the highest expression levels (13). However, the role of FXR in the kidney remains largely unknown. It has been previously reported that FXR may negatively regulate sterol regulatory element-binding protei...

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FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice

Cited by 18 publications

References 38 publications

Bile acid-FXRα pathways regulate male sexual maturation in mice

Bile acid-FXRα pathways regulate male sexual maturation in mice

Farnesoid X receptor is essential for the survival of renal medullary collecting duct cells under hypertonic stress

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

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