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

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 (S1P(2)) in hepatocytes in rats in vitro. A potential role of S1P and S1P(2) in liver regeneration and fibrosis was examined in S1P(2)-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 S1P(2)-deficient mice after a single carbon tetrachloride (CCl(4)) injection. After dimethylnitrosamine (DMN) administration with a lethal dose, PCNA staining in hepatocytes was enhanced at 48 h and survival rate was higher in S1P(2)-deficient mice. Serum aminotransferase level was unaltered in those mice compared with wild-type mice in both CCl(4)- and DMN-induced liver injury, suggesting that S1P(2) inactivation accelerated regeneration not as a response to enhanced liver damage. After chronic CCl(4) administration, fibrosis was less apparent, with reduced expression of smooth-muscle alpha-actin-positive cells in the livers of S1P(2)-deficient mice, suggesting that S1P(2) inactivation ameliorated CCl(4)-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 S1P(2).

• Authors: 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
• Journal: Journal of lipid research (J Lipid Res) Vol. 50 Issue 3 Pg. 556-564 (Mar 2009) ISSN: 0022-2275 [Print] United States
• PMID: 18955732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• Proliferating Cell Nuclear Antigen
• Receptors, Lysosphingolipid
• Sphingosine-1-Phosphate Receptors
• sphingosine-1-phosphate receptor-2, mouse
• sphingosine 1-phosphate
• Carbon Tetrachloride
• Dimethylnitrosamine
• Sphingosine

Topics

• Animals
• Carbon Tetrachloride (toxicity)
• Dimethylnitrosamine (toxicity)
• Female
• Hepatocytes (drug effects, metabolism, pathology)
• Liver (injuries, metabolism, pathology)
• Liver Cirrhosis (chemically induced, metabolism, pathology)
• Liver Regeneration (genetics, physiology)
• Lysophospholipids (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Proliferating Cell Nuclear Antigen (metabolism)
• Receptors, Lysosphingolipid (deficiency, genetics, metabolism)
• Sphingosine (analogs & derivatives, metabolism)
• Sphingosine-1-Phosphate Receptors