HbG200-mediated preinduction of heme oxygenase-1 improves bile flow and ameliorates pericentral downregulation of Bsep and Mrp2 following experimental liver ischemia and reperfusion.

Abstract

We studied the downregulation of hepatobiliary transport systems and the effect of pharmacological heme oxygenase-1 (HO-1) preinduction by Hemoglobin-Glutamer 200 (HbG200) in cold ischemia-reperfused rat liver (I/R). Cold I/R reduced bile flow in the reperfusion period from 3.10±0.10 ml/3 h to 0.54±0.20 ml/3 h (p<0.05) and biliary taurocholate excretion from 45.9±13.81 μmol/3 h to 1.87±0.46 μmol/3 h (p<0.05). Mrp2, Bsep and Ntcp peak immunofluorescence in pericentral hepatocytes decreased to 79.0±2.6% (p<0.001), 80.6±8.4% (p<0.05) and 65.8±5.0% (p<0.01), respectively. Pre-induction of HO-1 by HbG200 was largely confined to pericentral hepatocytes. HO-1 induction attenuated the decreased bile flow (0.91±0.16 ml/3 h, p<0.05) and canalicular taurocholate secretion (4.33±1.71 μmol/3 h, p<0.05). Bsep and Mrp2 peak immunofluorescence in pericentral hepatocytes was largely restored. Activation of JNK and Fyn by cold I/R was significantly attenuated by HO-1. Inhibiting HO activity by tin protoporphyrin IX after HbG200 administration reversed the effect on bile flow and canalicular transporter expression. In conclusion, pericentral downregulation of Bsep and Mrp2 following cold I/R is ameliorated by inducing HO-1 and was associated with diminished hepatocellular JNK and Fyn signaling. HO-1 may serve as a therapeutic target to attenuate hepatocellular cholestasis following I/R injury.

• Authors: Markus G Donner, Stefan A Topp, Patricia Cebula, Anna Krienen, Thor Gehrmann, Annika Sommerfeld, Roland Reinehr, Arne Macher, Diran Herebian, Ertan Mayatepek, Benedikt H Pannen, Wolfram T Knoefel, Dieter Häussinger
• Journal: Biological chemistry (Biol Chem) Vol. 394 Issue 1 Pg. 97-112 (Jan 2013) ISSN: 1437-4315 [Electronic] Germany
• PMID: 23096566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Abcb11 protein, rat
• Abcc2 protein, rat
• Hemoglobins
• hemoglobin glutamer-200
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Bile (metabolism)
• Disease Models, Animal
• Down-Regulation
• Heme Oxygenase (Decyclizing) (metabolism)
• Hemoglobins (metabolism)
• Ischemia (enzymology, metabolism)
• Male
• Rats
• Rats, Wistar
• Reperfusion Injury (enzymology, metabolism)