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Nr1h4  -  nuclear receptor subfamily 1, group H,...

Mus musculus

Synonyms: AI957360, Bar, Bile acid receptor, FXR, Farnesoid X-activated receptor, ...
 
 
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Disease relevance of Nr1h4

  • CONCLUSIONS: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice [1].
  • Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity [2].
  • In the present study, we show that LPS significantly decreases farnesoid X receptor (FXR) mRNA in mouse liver as early as 8 h after LPS administration, and this decrease was dose-dependent with the half-maximal effect observed at 0.5 microg/100 g of body weight [3].
  • PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists [4].
  • However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear [5].
 

Psychiatry related information on Nr1h4

  • The bile acid receptor farnesoid X receptor (FXR) is a key regulator of hepatic defense mechanisms against bile acids [6].
 

High impact information on Nr1h4

 

Chemical compound and disease context of Nr1h4

  • FXR-null mice developed severe fatty liver and elevated circulating FFAs, which was associated with elevated serum glucose and impaired glucose and insulin tolerance [10].
  • To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4-bis[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP), followed by the CA diet [11].
  • In vivo administration of 6-ECDCA protects against cholestasis induced by estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders [12].
  • Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement [13].
  • Mice lacking the farnesoid X receptor (FXR) involved in the maintenance of hepatic bile acid levels are highly sensitive to cholic acid-induced liver toxicity [14].
 

Biological context of Nr1h4

 

Anatomical context of Nr1h4

  • Bile acid signaling through FXR induces intracellular adhesion molecule-1 expression in mouse liver and human hepatocytes [17].
  • FXR knockout (FXR-/-) and wild-type (FXR+/+) mice were subjected to common bile duct ligation (CBDL) [5].
  • Peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta/delta, and PPARgamma, liver X receptor (LXR)alpha and LXRbeta, farnesoid X receptor (FXR), and retinoid X receptor (RXR)alpha, RXRbeta, and RXRgamma mRNA levels were significantly decreased in the livers of 19-day pregnant mice [16].
  • In FXR-/- skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted [10].
  • These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow [18].
 

Associations of Nr1h4 with chemical compounds

  • In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR [4].
  • Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA [17].
  • We show here that FXR plays a key regulatory role in glucose homeostasis [10].
  • In skeletal muscle, which does not express FXR, triglyceride and FFA levels were increased, and we propose that their inhibitory effects account for insulin resistance in that tissue [10].
  • MRP2 mRNA levels were induced following treatment of human or rat hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands [19].
 

Enzymatic interactions of Nr1h4

  • In conclusion, Fxr(-/-) mice detoxify accumulating bile acids in the liver by enhanced hydroxylation reactions probably catalyzed by Cyp3a11 [20].
 

Regulatory relationships of Nr1h4

  • In contrast, SHP reporter or BSEP reporter genes were activated to similar degrees by each of the FXR isoforms [21].
  • Taken together, the current data suggest that a small number of genes that currently include PLTP, apoE, and apoC-II, are induced in macrophages by activated LXR and in liver by activated FXR [22].
  • Other bile acids, such as chenodeoxycholic (CDCA), are agonists for the nuclear farnesoid X receptor (FXR) and regulate the expression of genes relevant for bile acid and cholesterol homeostasis [23].
 

Other interactions of Nr1h4

 

Analytical, diagnostic and therapeutic context of Nr1h4

  • Mobility shift assays demonstrated that the two stronger responding elements were able to bind FXR protein [26].
  • To investigate whether Fxr(-/-) mice differ in bile acid detoxification compared with wild-type mice, we performed a comprehensive analysis of bile acids extracted from liver, bile, serum, and urine of naive and common bile duct-ligated wild-type and Fxr(-/-) mice using electrospray and gas chromatography mass spectrometry [20].
  • Changes in the mRNA amounts in liver, kidney, small intestine, and testis in FXR-null mice fed with or without a supplement of 0.5% cholic acid in the diet were analyzed by semiquantitative RT-PCR [27].
  • In the current study, we performed microarray analysis using RNA from H295R cells infected with constitutively active FXR [28].
  • The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease [29].

References

  1. FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice. Wittenburg, H., Lyons, M.A., Li, R., Churchill, G.A., Carey, M.C., Paigen, B. Gastroenterology (2003) [Pubmed]
  2. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. Yamamoto, Y., Moore, R., Hess, H.A., Guo, G.L., Gonzalez, F.J., Korach, K.S., Maronpot, R.R., Negishi, M. J. Biol. Chem. (2006) [Pubmed]
  3. Repression of farnesoid X receptor during the acute phase response. Kim, M.S., Shigenaga, J., Moser, A., Feingold, K., Grunfeld, C. J. Biol. Chem. (2003) [Pubmed]
  4. A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. Shih, D.M., Kast-Woelbern, H.R., Wong, J., Xia, Y.R., Edwards, P.A., Lusis, A.J. J. Lipid Res. (2006) [Pubmed]
  5. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver. Zollner, G., Wagner, M., Fickert, P., Geier, A., Fuchsbichler, A., Silbert, D., Gumhold, J., Zatloukal, K., Kaser, A., Tilg, H., Denk, H., Trauner, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  6. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-{alpha}/beta in the adaptive response to bile acids. Zollner, G., Wagner, M., Moustafa, T., Fickert, P., Silbert, D., Gumhold, J., Fuchsbichler, A., Halilbasic, E., Denk, H., Marschall, H.U., Trauner, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  7. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Sinal, C.J., Tohkin, M., Miyata, M., Ward, J.M., Lambert, G., Gonzalez, F.J. Cell (2000) [Pubmed]
  8. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Moschetta, A., Bookout, A.L., Mangelsdorf, D.J. Nat. Med. (2004) [Pubmed]
  9. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Zhang, Y., Castellani, L.W., Sinal, C.J., Gonzalez, F.J., Edwards, P.A. Genes Dev. (2004) [Pubmed]
  10. Farnesoid X receptor is essential for normal glucose homeostasis. Ma, K., Saha, P.K., Chan, L., Moore, D.D. J. Clin. Invest. (2006) [Pubmed]
  11. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. Guo, G.L., Lambert, G., Negishi, M., Ward, J.M., Brewer, H.B., Kliewer, S.A., Gonzalez, F.J., Sinal, C.J. J. Biol. Chem. (2003) [Pubmed]
  12. Role of FXR in regulating bile acid homeostasis and relevance for human diseases. Rizzo, G., Renga, B., Mencarelli, A., Pellicciari, R., Fiorucci, S. Curr. Drug Targets Immune Endocr. Metabol. Disord. (2005) [Pubmed]
  13. Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity. Kitada, H., Miyata, M., Nakamura, T., Tozawa, A., Honma, W., Shimada, M., Nagata, K., Sinal, C.J., Guo, G.L., Gonzalez, F.J., Yamazoe, Y. J. Biol. Chem. (2003) [Pubmed]
  14. Role of farnesoid X receptor in the enhancement of canalicular bile acid output and excretion of unconjugated bile acids: a mechanism for protection against cholic acid-induced liver toxicity. Miyata, M., Tozawa, A., Otsuka, H., Nakamura, T., Nagata, K., Gonzalez, F.J., Yamazoe, Y. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  15. Amplification and overexpression of oncogene Mdm2 and orphan receptor gene Nr1h4 in immortal PRKDC knockout cells. Ai, R., Sandoval, A., Chen, D.J., Burma, S., Labhart, P. Mol. Biol. Rep. (2004) [Pubmed]
  16. Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy. Sweeney, T.R., Moser, A.H., Shigenaga, J.K., Grunfeld, C., Feingold, K.R. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  17. Bile acid signaling through FXR induces intracellular adhesion molecule-1 expression in mouse liver and human hepatocytes. Qin, P., Borges-Marcucci, L.A., Evans, M.J., Harnish, D.C. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  18. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Inagaki, T., Moschetta, A., Lee, Y.K., Peng, L., Zhao, G., Downes, M., Yu, R.T., Shelton, J.M., Richardson, J.A., Repa, J.J., Mangelsdorf, D.J., Kliewer, S.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. Kast, H.R., Goodwin, B., Tarr, P.T., Jones, S.A., Anisfeld, A.M., Stoltz, C.M., Tontonoz, P., Kliewer, S., Willson, T.M., Edwards, P.A. J. Biol. Chem. (2002) [Pubmed]
  20. Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. Marschall, H.U., Wagner, M., Bodin, K., Zollner, G., Fickert, P., Gumhold, J., Silbert, D., Fuchsbichler, A., Sjövall, J., Trauner, M. J. Lipid Res. (2006) [Pubmed]
  21. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. Zhang, Y., Kast-Woelbern, H.R., Edwards, P.A. J. Biol. Chem. (2003) [Pubmed]
  22. Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. Mak, P.A., Kast-Woelbern, H.R., Anisfeld, A.M., Edwards, P.A. J. Lipid Res. (2002) [Pubmed]
  23. Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: role of the farnesoid X receptor. Campana, G., Pasini, P., Roda, A., Spampinato, S. Biochem. Pharmacol. (2005) [Pubmed]
  24. Regulation of the mouse organic solute transporter {alpha}-beta, Ost{alpha}-Ostbeta, by bile acids. Frankenberg, T., Rao, A., Chen, F., Haywood, J., Shneider, B.L., Dawson, P.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  25. LXR Alpha Transactivates Mouse Organic Solute Transporter Alpha and Beta via IR-1 Elements Shared with FXR. Okuwaki, M., Takada, T., Iwayanagi, Y., Koh, S., Kariya, Y., Fujii, H., Suzuki, H. Pharm. Res. (2007) [Pubmed]
  26. Pregnane X receptor is a target of farnesoid X receptor. Jung, D., Mangelsdorf, D.J., Meyer, U.A. J. Biol. Chem. (2006) [Pubmed]
  27. Regulation of drug transporters by the farnesoid X receptor in mice. Maeda, T., Miyata, M., Yotsumoto, T., Kobayashi, D., Nozawa, T., Toyama, K., Gonzalez, F.J., Yamazoe, Y., Tamai, I. Mol. Pharm. (2004) [Pubmed]
  28. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. Lee, H., Zhang, Y., Lee, F.Y., Nelson, S.F., Gonzalez, F.J., Edwards, P.A. J. Lipid Res. (2006) [Pubmed]
  29. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. Liu, Y., Binz, J., Numerick, M.J., Dennis, S., Luo, G., Desai, B., MacKenzie, K.I., Mansfield, T.A., Kliewer, S.A., Goodwin, B., Jones, S.A. J. Clin. Invest. (2003) [Pubmed]
 
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