Identification of a nuclear receptor that is activated by farnesol metabolites

Forman, Barry M.; Goode, Elizabeth; Chen, Jasmine; Oro, Anthony E.; Bradley, David J.; Perlmann, Thomas; Noonan, Daniel J.; Burka, Leo T.; McMorris, Trevor C.; Lamph, William W.; Evans, Ronald M.; Weinberger, Cary

doi:10.1016/0092-8674(95)90530-8

Cited by 1,067 publications

(794 citation statements)

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“…Hirano,et al page 13 receptor, farnesoid X receptor (Wang et al, 1999;Makishima et al, 1999;Parks et al, 1999); farnesoid X receptor binds to DNA as a heterodimer with retinoid X receptor, recognizing an inverted hexanucleotide repeat separated by a single base (an IR-1 motif) (Forman et al, 1995). Although no IR-1 element has been identified in the RANTES promoter, further study should examine whether interaction between farnesoid X receptor and PPAR is related to inhibitory effects of fibrates on chenodeoxycholic acid-induced RANTES gene expression.…”

Section: Discussionmentioning

confidence: 99%

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Hirano

Fujii

et al. 2002

European Journal of Pharmacology

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Fibrates, hypolipidemic agents, are reported to be effective in treatment of primary biliary cirrhosis. However, the mechanism involved in therapeutic benefits of fibrates in primary biliary cirrhosis remains unknown. In contrast, hepatic regulated upon activation, normal T-cell expressed and secreted (RANTES) is increased in patients with primary biliary cirrhosis and bile acids up-regulate RANTES expression in hepatocytes. The role of fibrates in bile acid-induced RANTES expression was investigated in human hepatoma cells; 100 µM of bezafibrate and fenofibrate decreased expression of chenodeoxycholic acid-induced RANTES mRNA and protein. In addition, luciferase enzyme assay using RANTES promoter-luciferase reporter plasmid revealed that 100 µM of bezafibrate and fenofibrate transcriptionally reduced chenodeoxycholic acid-induced RANTES gene expression. Moreover, bezafibrate clearly repressed DNA-binding activity of nuclear factor-B (NF-B) induced by chenodeoxycholic acid. Therefore, fibrates might be inhibitory agents of inflammatory cell migration by RANTES to the liver in patients with primary biliary cirrhosis, possibly indicating that fibrates are therapeutic agents in primary biliary cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Hirano

Fujii

et al. 2002

European Journal of Pharmacology

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“…FXR was isolated from the cDNA library of rat liver originally, and was named farnesoate receptor because it was activated by superphysiological concentrations of farnesoate [11]. In 1999, some groups found that bile acids were the natural ligands of FXR, which is since known as the BAR [12,13].…”

Section: Introductionmentioning

confidence: 99%

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

2010

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Objective The aim of this study was to explore the role of farnesoid X receptor (FXR) in liver lipid metabolism of non-alcoholic fatty liver disease (NAFLD) patients. Methods In this study, pathology and clinical criteria confirmed NAFLD in patients. Fatty acid synthetase (FAS)-positive liver cells were visualized by laser scanning confocal microscopy. Levels of FXR, liver X receptor (LXR), sterol regulatory element binding protein 1C (SREBP-1C), and small heterodimer partner (SHP) proteins were detected by Western blot. FXR, LXR, and SHP mRNA levels were measured by real-time PCR. Results In patients with NAFLD, a significant positive relationship between the degree of hepatic steatosis and serum triglycerides and cholesterol (correlation coefficient [ 0.5, P \ 0.05) was seen. The NAFLD patients had more FAS protein in liver, which suggests that there could have been more of fatty acid synthesis in hepatic cells (P \ 0.05). The levels of FXR protein and mRNA were decreased in patients with NAFLD (P \ 0.05), while those of LXR and SREBP-1C were increased (P \ 0.05). The levels of SREBP-1C positively correlated with the degree of hepatic steatosis. There were no differences between the levels of SHP protein and mRNA both in NAFLD patients and normal controls (P [ 0.05).Conclusion Our data showed that the decreased expression of hepatic FXR is associated with an increased expression of LXR, SREBP-1C, and hepatic triglyceride synthesis; furthermore, increased SREBP-1C is associated with the degree of hepatic steatosis in the NAFLD patients.

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“…The farnesoid X receptor (FXR, NR1H4) was initially isolated in 1995 as an orphan nuclear receptor activated by farnesol, a metabolic intermediate of the mevalonate pathway [1]. In subsequent studies, FXR was deorphanized by the identification of bile acids (in particular chenodeoxycholic acid, CDCA) as cognate ligands [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…In early studies, FXR was shown to exhibit a rather narrow tissue distribution, its expression being restricted to the liver, the intestine, the kidney and the adrenal gland [1]. In the liver and the gastrointestinal tract, it functions as a bile acid sensor and regulates bile acid homeostasis, lipid and glucose metabolism, and hepatic regeneration [6].…”

Section: Introductionmentioning

confidence: 99%

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

Journé

Durbecq

Chaboteaux

et al. 2008

Breast Cancer Res Treat

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International audienceThe farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is normally produced in the liver and the gastrointestinal tract, where it acts as a bile acid sensor. It has been recently detected in breast cancer cell lines and tissue specimens. The expression of FXR was scored (0–8) by immunohistochemistry on 204 breast cancer samples and correlated with established cancer biomarkers. Moreover, the effect of the FXR activator chenodeoxycholic acid (CDCA) was determined on cell proliferation and estrogen receptor regulation/activation in breast cancer cell lines. FXR was detected in 82.4% of samples with a high median expression score of 5. FXR expression significantly correlated with estrogen receptor (ER) expression ( = 0.009) and luminal-like markers. In ER-positive tumors, FXR expression was significantly correlated with the proliferation marker Ki-67 ( < 0.001) and the nodal status ( = 0.028), but only so in postmenopausal women, suggesting that lack of estrogens may disclose the association between FXR and cell proliferation. In vitro experiments confirmed clinical data since CDCA stimulated the proliferation of ER-positive cells only in steroid-free medium, a stimulation inhibited upon siRNA-silencing of FXR expression as well as ER blockade by antiestrogens. Moreover, co-immunoprecipitation experiments revealed that CDCA activated-FXR interacted with ER. These results suggest that ER-positive breast tumors could be stimulated to proliferate via a crosstalk between FXR and ER, particularly in a state of estrogen deprivation (menopause, aromatase inhibitors)

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Identification of a nuclear receptor that is activated by farnesol metabolites

Cited by 1,067 publications

References 37 publications

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

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