Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2

Hitoshi Ikeda, Naoko Watanabe, Isao Ishii, Tatsuo Shimosawa, Yukio Kume, Tomoaki Tomiya, Yukiko Inoue, Takako Nishikawa, Natsuko Ohtomo, Yasushi Tanoue, Satoko Iitsuka, Ryoto Fujita, Masao Omata, Jerold Chun, Yutaka Yatomi

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83 Citations (Scopus)

Abstract

Sphingosine 1-phosphate (S1P), a bioactive lipid mediator, stimulates proliferation and contractility in hepatic stellate cells, the principal matrix-producing cells in the liver, and inhibits proliferation via S1P receptor 2 (S1P2) in hepatocytes in rats in vitro. A potential role of S1P and S1P2 in liver regeneration and fibrosis was examined in S1P2-deficient mice. Nuclear 5-bromo-2′-deoxy-uridine labeling, proliferating cell nuclear antigen (PCNA) staining in hepatocytes, and the ratio of liver weight to body weight were enhanced at 48 h in S1P2-deficient mice after a single carbon tetrachloride (CCl4) injection. After dimethylnitrosamine (DMN) administration with a lethal dose, PCNA staining in hepatocytes was enhanced at 48 h and survival rate was higher in S1P2-deficient mice. Serum aminotransferase level was unaltered in those mice compared with wild-type mice in both CCl4-and DMN-induced liver injury, suggesting that S1P2 inactivation accelerated regeneration not as a response to enhanced liver damage. After chronic CCl4 administration, fibrosis was less apparent, with reduced expression of smooth-muscle α-actin-positive cells in the livers of S1P2-deficient mice, suggesting that S1P2 inactivation ameliorated CCl4-induced fibrosis due to the decreased accumulation of hepatic stellate cells. Thus, S1P plays a significant role in regeneration and fibrosis after liver injury via S1P2.

Original languageEnglish
Pages (from-to)556-564
Number of pages9
JournalJournal of lipid research
Volume50
Issue number3
DOIs
Publication statusPublished - 2009 Apr

Keywords

  • Hepatic myofibroblast
  • Hepatic stellate cell
  • Hepatocyte
  • Liver fibrosis
  • Liver regeneration

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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    Ikeda, H., Watanabe, N., Ishii, I., Shimosawa, T., Kume, Y., Tomiya, T., Inoue, Y., Nishikawa, T., Ohtomo, N., Tanoue, Y., Iitsuka, S., Fujita, R., Omata, M., Chun, J., & Yatomi, Y. (2009). Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. Journal of lipid research, 50(3), 556-564. https://doi.org/10.1194/jlr.M800496-JLR200