and polygenic mouse models (SFB/TRR 57)

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Expression analysis and
transporters in human liver
transcriptional
regulation
of
organic
anion
The liver is a key site for metabolism and elimination of xenobiotics and endogenous
compounds from sinusoidal blood. The hepatic drug uptake occurs via specific
transport proteins at the basolateral surface, such as organic anion transporting
polypeptides (OATPs), organic anion transporters (OATs) and organic cation
transporters (OCTs), all members of the solute carrier gene family (SLC). These
transporters are regulated at the transcriptional level by nuclear receptors, xenobiotic
and endogenous ligands such as bile acids. We have shown recently that the liver
specific hOAT7 (SLC22A9), which mediates transport of sulfated compounds,
estrogens and short chain fatty acids, is transactivated by hepatocyte nuclear factor1a. Preliminary data suggest that hOAT7 is repressed by bile acids. The exact
mechanism by which bile acids repress hOAT7 gene transcription will be elucidated
by cell culture experiments with subsequent OAT7 mRNA and protein detection, siRNA experiments, studies on the OAT7 promoter using luciferase reporter gene
assays and electrophoretic mobility shift assay. The effect of bile acids on drug
transporters is of major interest, as altered expression may influence drug response
in patients with cholestatic liver disease. Hence, the results from in vivo studies will
be proofed in vitro by assessment of expression levels of all human liver OATs,
namely hOAT2, hOAT5 and hOAT7, in human liver tissue of healthy subjects and in
conditions of cholestatic liver disease. In addition, polymorphisms in coding and
promoter regions of these OATs will be correlated to the expression phenotype in
human liver tissue.
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