Role of heme oxygenase-1 and kupffer cells in the production of bilirubin in the rat liver

K. I. Hirano, T. Kobayashi, T. Watanabe, T. Yamamoto, G. Hasegawa, K. Hatakeyama, M. Suematsu, M. Naito

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Abstract

Heme oxygenase (HO)-1, the heme-degrading enzyme in macrophages, plays a key role in bilirubin metabolism. HO-1 is expressed in various tissue macrophages, especially Kupffer cells. This study aimed to examine the roles of macrophages and HO-1 in the modulation of heme catabolism in rat livers. Rats treated with or without liposome-encapsulated dichloromethylene diphosphonate, a macrophage-depleting reagent, were administered with heat-denatured red blood cells (h-RBC), and the time course of the biliary output of bilirubin and the expressions of HO-1 mRNA and protein were monitored. Immunohistochemistry in the control rat liver revealed that Kupffer cells constitute a major cellular component expressing HO-1, while hepatocytes exhibited little expression. The levels of HO-1 expression in Kupffer cells were elevated immediately after injection of h-RBC. In Kupffer cell-depleted livers, however, HO-l-expressing cells were not detected even after h-RBC administration. HO-1 mRNA levels were elevated at 2 h after administration of h-RBC in control rat livers, while they were very low in Kupffer cell-depleted rat livers. The control and Kupffer cell-depleted groups exhibited distinct time courses of biliary bilirubin excretion. In the untreated control rats, total bilirubin excretion increased about two-fold at 5 h after h-RBC administration. In contrast, the Kupffer cell-depleting treatment decreased the level of bilirubin production; administration of h-RBC to Kupffer cell-depleted rats did not accelerate the generation of bilirubin. These results suggest that Kupffer cells serve both as a sensor for scenesent RBC clearance and an effector that upregulates heme-degrading capacity and bilirubin production.

Original languageEnglish
Pages (from-to)169-178
Number of pages10
JournalArchives of Histology and Cytology
Volume64
Issue number2
DOIs
Publication statusPublished - 2001 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Histology

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    Hirano, K. I., Kobayashi, T., Watanabe, T., Yamamoto, T., Hasegawa, G., Hatakeyama, K., Suematsu, M., & Naito, M. (2001). Role of heme oxygenase-1 and kupffer cells in the production of bilirubin in the rat liver. Archives of Histology and Cytology, 64(2), 169-178. https://doi.org/10.1679/aohc.64.169