Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo

Takashi Kobayashi, Yoshinobu Sato, Satoshi Yamamoto, Toshiyuki Takeishi, Ken Ichiro Hirano, Takaoki Watanabe, Isao Kurosaki, Yoshio Shirai, Makoto Naito, Makoto Suematsu, Katsuyoshi Hatakeyama

Research output: Contribution to journalArticle

Abstract

Kupffer cells constitute a major source of heme oxygenase (HO)-1, a heme-degrading enzyme. This study aimed to examine roles of Kupffer cells in the modulation of accelerated heme catabolism in ischemia-reperfused rat livers. Livers treated with or without liposome-encapsulated clodronate, a Kupffer cell-depleting reagent, underwent a 20-min ligation of the portal vein followed by reperfusion (I/R), and the time course of the biliary output of bilirubin, the terminal heme-degrading product, and the expression of HO-1 mRNA and protein were monitored. HO-1 mRNA levels were elevated at 3-12hrs after I/R in both control and Kupffer cell-depleted rats. Immunohistochemistry in the controls revealed that Kupffer cells constitute a major cellular component expressing HO-1, while hepatocytes exhibited little expression. On the other hand, in Kupffer cell-depleted livers, periportal hepatocytes displayed a marked HO-1 expression. Under these conditions the two groups exhibited distinct profiles of biliary bilirubin excretion: In the controls, total bilirubin excretion increased 8-fold and peaked at 10hrs after I/R. On the other hand, the Kupffer cell-depleting treatment significantly accelerated the initial rise in bilirubin which peaked at 4hrs, and the total amount of bilirubin excreted within the initial 10hrs after reperfusion was reduced by 50% as compared with the controls. These results suggest that Kupffer cells serve as an I/R sensor that upregulates heme-degrading capacity and ameliorates excessive excretion of bilirubin into bile, functioning as a sink-buffer of bilirubin metabolism.

Original languageEnglish
Pages (from-to)S109-S117+S131
JournalJapanese Pharmacology and Therapeutics
Volume31
Issue numberSUPPL. 1
Publication statusPublished - 2003 Dec 1

Keywords

  • Heme oxygenase-1 (HO-1)
  • Ischemia/reperfusion
  • Kupffer cells
  • Liver
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Kobayashi, T., Sato, Y., Yamamoto, S., Takeishi, T., Hirano, K. I., Watanabe, T., Kurosaki, I., Shirai, Y., Naito, M., Suematsu, M., & Hatakeyama, K. (2003). Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo. Japanese Pharmacology and Therapeutics, 31(SUPPL. 1), S109-S117+S131.