Journal of Lipid Research (Mar 2009)
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
Affiliations
- Hitoshi Ikeda
- 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
- Naoko Watanabe
- 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
- Isao Ishii
- 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
- Tatsuo Shimosawa
- 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
- Yukio Kume
- 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
- Tomoaki Tomiya
- 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
- Yukiko Inoue
- 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
- Takako Nishikawa
- 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
- Natsuko Ohtomo
- 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
- Yasushi Tanoue
- 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
- Satoko Iitsuka
- 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
- Ryoto Fujita
- 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
- Masao Omata
- 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
- Jerold Chun
- 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
- 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
- Journal volume & issue
-
Vol. 50,
no. 3
pp. 556 – 564
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.
