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) is a transcription factor important to the
maintenance of liver phenotype among other organs. Absence of Hnf1
Hepatocyte nuclear factor 1
(HNF1
in mice
causes hepatic dysfunction resulting from disregulation of bile acid and cholesterol
homeostasis.
45
,
46
The alterations in bile acid transport are associated with changes in
the hepatic expression of Oatps such as Oatp1a1, Oatp1a5, Oatp1b2, and Oatp2b1,
which are markedly down-regulated.
46
,
47
The human
SLCO1B1
and
SLCO1B3
genes
contain functional HNF1
response elements in their proximal promoters,
48
a finding
that is consistent with their liver-selective expression. Various pathological conditions
such as inflammation are known to down-regulate the expression of HNF1
, leading
to decreased expression of hepatic OATPs.
49
The inducible expression of hepatic OATPs appears to result from bile acid-
mediated activation of the farnesoid X receptor (FXR).
50
The
SLCO1B3
gene is
directly transactivated by FXR, to cause an up-regulation in OATP1B3 expression
in a hepatically derived cell line.
51
Together with the notion that OATP1B3 acts as
a hepatic bile acid efflux transporter and its expression is maintained in cholestatic
liver disease, it appears that transactivation of
SLCO1B3
by FXR serves as a means
of cytoprotection in the face of elevated bile acid exposure.
24
OATP1B3 expression is decreased in hepatocellular carcinoma (HCC), coinci-
dent with increased levels of the transcription factor hepatocyte nuclear factor 3
).
52
(HNF3
interacts with negative response elements in the
SLCO1B3
promoter.
52
,
53
to suppress OATP1B3 expression. The
SLCO1B3
promoter
is also transactivated by the growth hormone- and prolactin-activated transcription
factor Stat5, as determined by cell-based reporter gene assays.
54
The physiological
implications of these findings remain to be clarified. Finally, OATP1B3 is expressed
exclusively in perivenous hepatocytes,
26
,
39
,
55
suggesting local transcriptional con-
trol of gene expression. It has been proposed that the diminished oxygen tension
in the perivenous liver stimulates the function of hypoxia inducible factor 1 (HIF1)
locally in the transactivation of a presumed response element in the first intron of the
SLCO1B3
gene.
55
Experimental confirmation of such a transcriptional mechanism is
required.
The pregnane X receptor (PXR) is a promiscuous, ligand-activated transcription
factor important to the inductive response to xenobiotics.
56
Given that a broad array
of hepatic drug detoxification genes are regulated by PXR,
57
it is not unexpected that
the expression of OATPs may be induced through this signaling pathway. Thus, rat
Slco1a4
gene expression has been shown to be directly regulated by pxr,
58
and hep-
atocyte Oatp1a4 levels are strongly induced in rats treated by the rodent pxr agonist
prenenolone carbonitrile.
59
In cultured human hepatocytes, OATP1B1 is modestly
induced by treatment with rifampin, suggesting that the
SLCO1B1
gene may be un-
der regulation by PXR.
60
Currently, it is unknown whether drug-mediated OATP1B1
induction occurs in vivo. Studies in breast carcinoma have demonstrated high levels
of OATP1A2 in tumor, which contrasts with the absence of expression in adjacent
tissue.
61
Moreover, the expression of OATP1A2 correlated with that of PXR, sugges-
tive of a potential mechanism for elevated transporter expression.
61
A direct role of
PXR in regulating OATP1A2 remains to be determined in addition to its relevance to
breast cancer pathogenesis and drug interactions.
It appears that HNF3
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