Famesoid X receptor FXR

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

The ecdysone receptor belongs to the same subfamily of nuclear receptors as the liver X receptor LXR, the famesoid X receptor FXR and the vitamin D receptor VDR [8,[48]. All these receptors bind steroid-related compounds (oxysterol, bile acids and vitamin D). A detailed sequence alignment and a phylogenetic analysis encompassing 19 EcR protein sequences of various arthropods has been perfcxmed by Bonneton et al [46]. We will summarize here the main issues of this study. 

Figure 8.8. Biosynthesis of bile acids and the enterohepatic circulation. Bile acids are synthesized from cholesterol in the liver under feedback regulation of the nuclear orphan receptors famesoid X receptor (FXR) and lignane X receptor (LXR). They are stored in the gallbladder and released through the bile duct into the duodenum, where they aid in the digestion of dietary fats. Intestinal uptake of bile acids takes place alongthe entire length of the small intestine, but active reabsorption is confined to the distal ileum to minimize loss of bile salts in the feces. The portal circulation carries bile acids from the intestine to the liver, where they are actively absorbed by hepatoc5Tesand secreted into bile.

Expression of IBABP and ASBT is regulated by the famesoid X receptor (FXR), a nuclear orphan receptor (246, 247). A specific binding site for F3 was found on the promotor region of the IBABP gene, named bile acid response element (BARE) (248). The response was greatest in the presence of chenodeoxy-cholic acid (CDCA), whereas cholic acid was much less effective and the secondary bile acids deoxycholic and lithocholic acid had variable responses. 

To create xenobiotic receptor reporter transgenic mice that also express a luciferase reporter gene under the control of the xenobiotic receptor responsive elements. Such nuclear receptor reporter transgenic mice have been reported for a number of receptors, such as the estrogen receptor (ER) [85], famesoid X receptor (FXR) [86], and PPAR [87], These mice can be used to monitor the in vivo responses of these receptors to both xenobiotics and endobiotics. 

FIGURE 11.79 Famesoid X receptor agonists from benzopyran libraries. (From Nicolaou, K.C. et al., Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries, Org. Biomol. Chem., 1, 908, 2003.)... 

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