BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 207

changes in transporter activity, whereas transcriptional changes may be responsible
for more intermediate- and longer-term regulation of transport.
9.5. NUCLEAR RECEPTORS AS TRANSCRIPTIONAL REGULATORS
OF BILE ACID HOMEOSTASIS
Nuclear and steroid receptors form a large family of transcriptional regulators, with
over 100 members in all metazoan organisms and almost 50 members in humans. 46
Most nuclear/steroid receptors share a conserved overall structural design: a ligand-
independent activation function at the amino terminus, a central conserved DNA-
binding domain, and a carboxy-terminal region containing regions mediating ligand
binding, dimerization, and ligand-dependent transactivation. Most nuclear/steroid re-
ceptors bind to their DNA response elements as either hetero- or homodimers, which
is reflected in their preferred DNA-binding motifs typically containing two hexameric
half sites. These hexamers, the general consensus sequence for which is AGGTCA,
can be arranged as direct (DR), inverted (IR), or everted (ER) repeats, separated by a
variable and receptor-specific number of base pairs.
The full transcriptional activity of most, but not all, nuclear/steroid receptors de-
pends on a physical interaction by an agonist with their ligand-binding pocket. These
ligands are typically small lipophilic molecules such as hormones, fatty acids, oxys-
terols, or bile acids. Their binding induces a conformational shift in the carboxy
termini of the receptors, allowing their interaction with transcriptional coactivators. 47
These coactivators may act by modifying histones or other promoter-associated
proteins or by altering local chromatin structure in a way that increases the rate
of transcriptional initiation. Conversely, in the absence of an agonistic ligand, or when
bound to an antagonistic ligand, the carboxy termini of nuclear and steroid receptors
associate with transcriptional corepressors that render the proximal promoters less
permissive for transcription. The dependence of the transcriptional activity of most
nuclear and steroid receptors on specific ligands allows them to monitor intracellular
environment and to elicit rapid transcriptional responses to changes in the concentra-
tions of specific compounds.
9.5.1. FXR: The Master Regulator of Bile Acid Transport and Metabolism
The chief sensor of intracellular bile acid levels and the main executor of bile acid-
induced transcriptional programs is the nuclear receptor farnesoid X receptor (FXR). 48
Bile acids interact directly with the ligand-binding domain of FXR. In transactiva-
tion and coactivator recruitment assays, CDCA is the most efficient FXR activator,
followed by DCA and CA. 49 − 51 LCA alone can weakly activate FXR; however, it
strongly antagonizes CDCA-mediated stimulation of FXR. 52 This apparent antago-
nism of FXR function may contribute to LCA-induced cholestasis.
Bile acids are not the only ligands that interact with FXR directly. Recently, it
has been suggested that the oxysterol 22( R )-hydroxycholesterol, an intermediate in
the synthesis of bile acids and steroid hormones, can also interact directly with the