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Journal of Lipid Research, Vol. 50, 556-564, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Hitoshi Ikeda^1,*,, 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^** and Yutaka Yatomi^*

^* Department of Clinical Labo ratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan
^** Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA

^* This work was supported by the Japanese Society of Laboratory Medicine Fund for the Promotion of Scientific Research (H.I.) and by National Institutes of Health Grants NS-048478 and R01 DA-019674 (J.C.).

Published, JLR Papers in Press, October 27, 2008.

¹ To whom correspondence should be addressed. e-mail: ikeda-1im{at}h.u-tokyo.ac.jp

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 -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.

Supplementary key words liver regeneration • liver fibrosis • hepatocyte • hepatic stellate cell • hepatic myofibroblast

Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; BrdU, 5-bromo-2'-deoxy-uridine; CCl₄, carbon tetrachloride; DMN, dimethylnitrosamine; PCNA, proliferating cell nuclear antigen; S1P, sphingosine 1-phosphate

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