Bile-Acid Receptors FXR

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases 

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A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Molecules and cells, 11, 1079-1092. 

Kanaya, E., Shiraki, T., and Jingami, H. (2004) The nuclear bile acid receptor FXR is activated by PGC-1 alpha in a ligand-dependent manner. Biochem. J. 382, 913-921. 

Another nuclear receptor, called FXR, is activated by the binding of bile acids. Expressed in hepatocytes and intestinal epithelial cells, FXR plays a key role in regulating the en-terohepatlc circulation of bile acids. Bile acid-activated FXR stimulates the expression of Intracellular bile acid-binding protein (I-BABP) and of transport proteins (e.g., ABCBll, NTCP) that mediate cellular export and Import of bile acids (see Figure 18-11). In contrast, active FXR represses the expression of cholesterol 7a-hydroxylase, thereby decreasing the synthesis of bile acids from cholesterol in the liver—another example of end-product Inhibition of a metabolic pathway. Both FXR and LXR function as heterodimers with the nuclear receptor RXR. 

Farnesoid X receptor (FXR) and liver X receptors (LXRs) belong to the same NR family as PXR and CAR. Their primary role lies in cholesterol and bile acid metabolism regulation. Like many NRs of this family, FXR heterodimerizes with RXR in vivo [46]. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Bile acids are also natural ligands for the farnesoid X receptor (FXR), a receptor that belongs to the nuclear hormone receptor superfamily. The hydrophobic bile acid chenodeoxycholic acid (CDCA) is the most potent... 

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. 

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