BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 209

receptor that typically utilizes drugs and xenobiotics as its ligands. 66 In response to
these ligands, PXR induces the expression of genes encoding proteins involved in drug
detoxification and elimination pathways. In addition to xenobiotics, certain bile acids,
such as the highly toxic LCA, can serve as agonistic ligands for PXR. 67 , 68 Indeed,
activation of PXR can protect mouse livers against LCA-mediated injury. 67 Double-
knockout mice lacking both FXR and PXR exhibit more severe disturbances of bile
acid metabolism than mice lacking only one of the nuclear receptors, demonstrating
that both contribute to bile acid homeostasis. 69 PXR is a master regulator of the gene
encoding the CYP3A4 enzyme, 70 which, in addition to its role in detoxifying xeno-
biotics, also metabolizes bile acids to less toxic and more easily excreted derivatives.
Thus, by being both activators of the CYP3A4 gene and substrates of the CYP3A4
enzyme, bile acids can initiate a hepatoprotective feedforward loop via PXR. Similar
to PXR, VDR can utilize the toxic secondary bile acid LCA as an agonistic ligand. 71
Whereas VDR is expressed only weakly in hepatocytes, it is present abundantly in
enterocytes. It is thus likely to play a more prominent role in the intestine in response
to LCA. In addition to PXR, VDR can also transactivate the CYP3A4 gene. Thus,
VDR activated by elevated levels of LCA in the intestine may, in a feedforward man-
ner, contribute to enhanced expression of the CYP3A4 enzyme, which is capable of
detoxifying LCA.
Common to all three nuclear receptors that can utilize bile acids as ligands (i.e.,
FXR, PXR, VDR) is that they all bind to their respective DNA response elements as
heterodimers with the nuclear receptor RXR, with very few exceptions. Positive or
negative effects on the transcriptional activity of RXR-containing heterodimers by the
RXR ligand 9- cis -retinoic acid appear to depend on the exact promoter context. 72 , 73

9.5.3. Bile Acid-Induced Transcriptional Repressor SHP

FXR can also negatively regulate the rate of transcription from specific promoters.
In rare cases, FXR is known to repress its target genes, such as those encoding the
human apolipoprotein A-I 74 and human apolipoprotein C-III, 75 through direct binding
to the promoter. However, FXR more commonly mediates negative transcriptional
responses to elevated levels of bile acids indirectly, through inducing expression
of its target gene encoding the transcriptional repressor called small heterodimer
partner , SHP. SHP is an atypical member of the nuclear receptor family; it does
not contain a DNA-binding domain and does not depend on a ligand for its activity.
Instead, it interacts directly with a variety of DNA-bound transcriptional activators,
interfering with their transcriptional activity. Although SHP can suppress the activity
of transcription factors from certain other families, it most commonly targets other
nuclear receptors and steroid receptors (reviewed in ref. 76). Via the SHP pathway,
bile acids can influence the activities of a wider range of transcription factors than
only those nuclear receptors that are modulated by them directly.
Several mechanisms have been suggested for SHP-mediated suppression of trans-
activator proteins. SHP may compete with transcriptional coactivators over the same
or overlapping interaction surface on transactivators that are bound to the promoter
elements. 77 Alternatively, SHP may interfere with the binding of transactivators to