BILE ACID TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 210

their DNA response elements. 78 Additionally, SHP may recruit transcriptional core-
pressors to its target promoters, thus contributing to the reduced transcriptional rate
of a given promoter. 79
The importance of SHP in the control of bile acid homeostasis is indicated by the
fact that SHP-null mice exhibit an imbalance in bile acid metabolism and abnormal
responses when challenged with diets rich in bile acids. 80 , 81

9.6. FXR-DEPENDENT MECHANISMS THAT REGULATE HUMAN
BILE ACID TRANSPORTER GENES

We discuss next the FXR-dependent effects of bile acids on the expression of trans-
porter genes in hepatocytes and enterocytes. These concepts are summarized in Figure
9.2. It should be emphasized that although we focus on FXR-dependent effects by

BILE ACID EFFLUX BILE ACID UPTAKE

BLOOD

BLOOD

NTCP

ILEOCYTE
BASOLATERAL
MEMBRANE

HEPATOCYTE
BASOLATERAL
MEMBRANE

OST α OST β

GR

GR

FXR RXR

FXR RXR SHP

BILE
ACIDS

FXR RXR BILE

ACIDS

I-BABP

SHP FXR RXR

FXR RXR

GR GR

ILEOCYTE
APICAL
MEMBRANE

FXR RXR

RXR

RAR

BSEP

MRP2

ASBT

HEPATOCYTE
CANALICULAR
MEMBRANE

BILE
CANALICULUS

INTESTINAL LUMEN

BILE ACID UPTAKE BILE ACID EFFLUX

FIGURE 9.2. Bile acid-induced FXR-dependent transcriptional mechanisms that regulate the
genes encoding enterohepatic bile acid transporters. FXR activated by bile acids induces the
expression of the intestinal (OST /OST ) and hepatic (BSEP, MRP2) bile acid efflux systems,
as well as of the intestinal intracellular bile acid transporter (I-BABP), via direct binding to
its response elements in the respective regulatory promoter regions. FXR binds DNA as a
heterodimer with the nuclear receptor RXR. Decreased expression of the intestinal (ASBT)
and hepatic (NTCP) bile acid uptake transporters occurs by a mechanism that involves FXR
indirectly. In this cascade, bile acid-activated FXR induces the expression of the transcriptional
repressor SHP, which subsequently interferes with the activity of the transactivator proteins
that regulate the expression of the genes encoding bile acid-uptake systems. In the case of
the human SLC10A1 (NTCP) and SLC10A2 (ASBT) promoters, the transactivator targeted by
SHP is the steroid receptor GR. In the context of the human SLC10A2 promoter, the nuclear
receptor heterodimer RAR-RXR has been suggested as an alternative or parallel target for
SHP-mediated transcriptional suppression.