Identification of Farnesoid X Receptor β as a Novel Mammalian Nuclear Receptor Sensing Lanosterol

Otte, Kerstin; Kranz, Harald; Kober, Ingo; Thompson, Paul D; Hoefer, Michael; Haubold, B; Remmel, Bettina; Voß, H.; Kaiser, Carmen; Albers, M.; Cheruvallath, Zaccharias; Jackson, David J.; Casari, Georg; Koegl, Manfred; Pääbo, Svante; Mous, Jan; Kremoser, Claus; Deuschle, Ulrich

doi:10.1128/mcb.23.3.864-872.2003

Cited by 164 publications

(93 citation statements)

References 42 publications

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“…Our results confirmed the existence of the three known pseudogenes in the human genome including ⌿FXR␤, the only unprocessed pseudogene (Maglich et al 2001;Robinson-Rechavi et al 2001). Because the mouse and rat orthologs of FXR␤ are expressed (identified and experimentally proven to be active by one of the authors, J.W., and Otte et al 2003) and because FXR␤ may share some functions with FXR in cholesterol metabolism, it remains unclear under what circumstances FXR␤ was silenced and how its loss was tolerated and fixed in the ancestral primate population.…”

supporting

confidence: 73%

Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome

Zhang¹,

Burch²,

Cooney³

et al. 2004

Genome Res.

195

162

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Completion of the Rattus norvegicus genome sequence enabled a global inventory and analysis of the nuclear receptors (NRs) in three mammalian species. Forty-nine NR members were found in mouse, 48 in human. Forty-seven were found in the rat, with gaps at the locations expected for the other two. Pairwise comparisons of their distribution in rat, mouse, and human identified 11 syntenic NR gene blocks, including three small clusters of two or three closely related genes, each spanning 40 kb to 1700 kb. The exon structure of the ligand-binding domain suggests that exon shuffling has played a role in the evolution of this family. An invariant splice junction in all members of the NR family except LXRβ suggests a functional role for the intron. The ligand-binding domains of PXR and CAR are among the most divergent in the family. Their higher nucleotide substitution rates may be related to the central role played by these two NRs in the metabolism of the foreign compounds and may have resulted from limited positive selection

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supporting

confidence: 73%

Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome

Zhang¹,

Burch²,

Cooney³

et al. 2004

Genome Res.

195

162

View full text Add to dashboard Cite

show abstract

“…High levels of mRNA for FXR are also found in the kidney and adrenal gland, areas of the body not classically considered as being bile acid targets (1), whereas low levels of mRNA for FXR are present in a variety of tissues, including heart, ovary, thymus, eye, spleen, and testes (7,8). The roles of FXR in these tissues are not known, nor indeed is the potential of bile acids to act as its ligands.…”

mentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

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

212

163

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The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

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“…FXR is expressed in nonenterohepatic tissues, including high levels in the kidneys and adrenal gland, which are ''nonclassic'' bile acid targets (1), and low levels in the heart, vascular tissue, thymus, ovary, spleen, and testes (19,20). The functions of FXR in these nonenterohepatic tissues are poorly understood, particularly within humans.…”

Section: Introductionmentioning

confidence: 99%

The Farnesoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression

et al. 2006

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Bile acids are present at high concentrations in breast cysts and in the plasma of postmenopausal women with breast cancer. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. FXR was detected in normal and tumor breast tissue, with a high level of expression in ductal epithelial cells of normal breast and infiltrating ductal carcinoma cells. FXR was also present in the human breast carcinoma cells, MCF-7 and MDA-MB-468. Activation of FXR by high concentrations of ligands induced MCF-7 and MDA-MB-468 apoptosis. At lower concentrations that had no direct effect on viability, the FXR agonist GW4064 induced expression of mRNA for the FXR target genes, small heterodimer partner (SHP), intestinal bile acid binding protein, and multidrug resistance-associated protein 2 (MRP-2), and repressed the expression of the SHP target gene aromatase. In contrast to MRP-2, mRNA for the breast cancer target genes MDR-3, MRP-1, and solute carrier transporter 7A5 were decreased. Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel. Our findings show for the first time that FXR is expressed in breast cancer tissue and has multiple properties that could be used for the treatment of breast cancer.

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Identification of Farnesoid X Receptor β as a Novel Mammalian Nuclear Receptor Sensing Lanosterol

Cited by 164 publications

References 42 publications

Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome

Genomic Analysis of the Nuclear Receptor Family: New Insights Into Structure, Regulation, and Evolution From the Rat Genome

Expression and activation of the farnesoid X receptor in the vasculature

The Farnesoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression

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