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

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)


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
Issue number3
Publication statusPublished - 2009 Apr
Externally publishedYes


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

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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