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Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liver


Prof. Dr. med. Matthias Wettstein, Clinic for Gastroenterology, Hepatology and Infectiology, Universitätsklinikum Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.


Abstract: Aims: The aim of this study was to investigate the regulation of hepatic transport systems during liver regeneration.

Methods: A DNA oligonucleotide microarray was developed with probes for 400 transcripts. Data were confirmed using real-time PCR and on a functional level in the perfused rat liver. Liver homogenates were taken 3–48 h following 2/3-hepatectomy in rats and compared with sham-operated and non-operated controls.

Results: A more than two-fold increase or decrease of expression was obtained in 183 genes following partial hepatectomy and in 16 genes in sham-operated rats. A strong induction during liver regeneration was detected for the amino acid transporters LAT4, SN2 and sodium-dependent neutral amino acid transporter (ASCT)2, whereas amino acid transport system (ATA)2 and ATA3 expressions remained unchanged. The upregulation of ASCT2 may be responsible for the increase in sodium-dependent neutral amino acid influx important for liver cell proliferation. Expression of the osmolyte transporters Smit, TauT and Bgt1 was almost unchanged indicating that osmolytes are not involved in the cell volume increase during liver regeneration. The basolateral bile salt transporter Ntcp messenger RNA (mRNA) was significantly downregulated, whereas bile salt export pump (Bsep) and multidrug resistance protein (Mrp)2 expressions remained almost unchanged. An increased mRNA expression following partial hepatectomy was detected for organic anion transporting polypeptide (Oatp)5, Octn1, Octn2 and SGLT2. In contrast, Mrp6, Oatp 2, Oatp 3, Oatp 4 and Oatp 7 were downregulated. A five-fold upregulation at the protein level was shown for the Na+–K+–2Cl cotransporter sodium-potassium-2-chloride cotransporter (NKCC1).

Conclusions: The data show a differential regulation of hepatic transport systems during liver regeneration.