title: Obstructive cholestasis induces TNF-alpha- and IL-1 -mediated periportal downregulation of Bsep and zonal regulation of Ntcp, Oatp1a4, and Oatp1b2.
abstract: Inverse acinar regulation of Mrp2 and 3 represents an adaptive response to hepatocellular cholestatic injury. We studied whether obstructive cholestasis (bile duct ligation) and LPS treatment affect the zonal expression of Bsep (Abcb11), Mrp4 (Abcc4), Ntcp (Slc10a1), and Oatp isoforms (Slco1a1, Slco1a4, and slco1b2) in rat liver, as analyzed by semiquantitative immunofluorescence. Contribution of TNF-alpha and IL-1beta to transporter zonation in obstructive cholestasis was studied by cytokine inactivation. In normal liver Bsep, Mrp4, Ntcp, and Oatp1a1 were homogeneously distributed in the acinus, whereas Oatp1a4 and Oatp1b2 expression increased from zone 1 to 3. Glutamine synthetase-positive pericentral hepatocytes exhibited markedly lower Oatp1a4 expression than the remaining zone 3 hepatocytes. In cholestatic liver Bsep and Ntcp immunofluorescence in periportal hepatocytes significantly decreased to 66 +/- 4% (P < 0.01) and 67 +/- 7% (P < 0.05), whereas it was not altered in pericentral hepatocytes. Oatp1a4 was significantly induced in hepatocytes with a primarily low expression, i.e., in periportal hepatocytes and in glutamine synthetase-positive pericentral hepatocytes. Likewise, Oatp1b2 was upregulated in periportal hepatocytes. Mrp4 zonal induction was homogeneous. Inactivation of TNF-alpha and IL-1beta prevented periportal downregulation of Bsep. Recruitment of neutrophils and polymorphonuclear cells mainly occurred in the periportal zone. Likewise, IL-1beta induction was largely found periportally. No significant transporter zonation was seen following LPS treatment. In conclusion, zonal downregulation of Bsep in obstructive cholestasis is associated with portal inflammation and is mediated by TNF-alpha and IL-1beta. Periportal downregulation of Ntcp and induction of Oatp1a4 and Oatp1b2 may represent adaptive mechanisms to reduce cholestatic injury in hepatocytes with profound downregulation of Bsep and Mrp2.
authors.affiliation: Dept. of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine Univ. Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Markus_Donner@yahoo.de
authors.forename: Markus G
authors.initials: MG
authors.lastname: Donner
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schumacher
authors.forename: Ulrich
authors.initials: U
authors.lastname: Warskulat
authors.forename: Jane
authors.initials: J
authors.lastname: Heinemann
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D001651:Cholestasis, Extrahepatic / Q000378:metabolism*; D015536:Down-Regulation; D007375:Interleukin-1 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters / Q000378:metabolism*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D007375:Interleukin-1; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; C503597:Slco1a4 protein, rat; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; D014409:Tumor Necrosis Factor-alpha; C071908:sodium-bile acid cotransporter