TY - JOUR
T1 - Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2
AU - Ikeda, Hitoshi
AU - Watanabe, Naoko
AU - Ishii, Isao
AU - Shimosawa, Tatsuo
AU - Kume, Yukio
AU - Tomiya, Tomoaki
AU - Inoue, Yukiko
AU - Nishikawa, Takako
AU - Ohtomo, Natsuko
AU - Tanoue, Yasushi
AU - Iitsuka, Satoko
AU - Fujita, Ryoto
AU - Omata, Masao
AU - Chun, Jerold
AU - Yatomi, Yutaka
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
KW - Hepatic myofibroblast
KW - Hepatic stellate cell
KW - Hepatocyte
KW - Liver fibrosis
KW - Liver regeneration
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U2 - 10.1194/jlr.M800496-JLR200
DO - 10.1194/jlr.M800496-JLR200
M3 - Article
C2 - 18955732
AN - SCOPUS:64349089268
VL - 50
SP - 556
EP - 564
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 3
ER -