The serum ATX activity and plasma LPA level are increased in chronic hepatitis C in association with liver fibrosis. Our study may provide the first evidence showing a significant increase of both ATX and LPA in the blood under a specific disease.

DCP is a more effective tumor marker than AFP and AFP-L3. AFP-L3 showed comparable accuracy to AFP but no benefit was found in their combination. GP73 did not play a significant role in this context. Indices of tumor invasiveness were most closely associated with DCP.

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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 a-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 . Sphingosine 1-phosphate (S1P), which elicits a wide variety of cell responses (1), has emerged as a novel lipid intracellular mediator. S1P was shown to act as an intracellular second messenger of platelet-derived growth factor and serum in their mitogenic actions in cultured fibroblasts (2, 3), and furthermore, intracellular levels of S1P and ceramide were reported to determine cell survival or death (4, 5). However, evidence indicating that S1P also acts as an extracellular mediator has been reported; some of the diverse effects of S1P, such as stimulation of cell proliferation or contractility, are known to be sensitive to pertussis toxin (6) or ADP-ribosyltransferase C3 from Clostridium botulinum (7, 8), suggesting that S1P may activate a receptor coupled to G protein(s). Indeed, recent investigation has revealed that S1P acts through at least five high-affinity G proteincoupled receptors referred to as S1P 1-5 (9, 10). Regarding the source of S1P in vivo, it is shown to be stored in platelets (11), and recent data using conditional knockouts of sphingosine kinases support release of S1P from erythrocytes (12, 13). These findings suggest that S1P has normal in vivo roles as well as potentially pathophysiological roles as a circulating paracrine mediator, a view further supported by the phenotypes of S1P receptor mutants (10,14,15). S1P receptors are also expressed in the liver (14). To investigate the function of S1P in liver pathophysiology, we have determined the effect of S1P on liver cells in culture. We first demonstrated that S1P stimulates proliferation and contractility in rat hepati...

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