Significance of lysophospholipid mediators in the liver

Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phospahte (S1P) are gaining much attention as a lysophospholipid intercellular mediator, because they exert divergent effects on various cells, such as a regulation of cell proliferation, contraction or movement, via the same family of G protein-coupled receptors formerly called as EDGs. Of particular interest is the fact that plasma concentrations of LPA and S1P are very close to those causing various responses in vitro. However, their clinical significance is not clarified yet. In the cultured cells, LPA stimulates proliferation and contraction and inhibits apoptosis in rat hepatic stellate cells, and inhibits proliferation in rat hepatocytes. S1P also stimulates proliferation and con traction via SIP receptor S1P₂ in rat hepatic stellate cells, and inhibits proliferation via S1P₂ in rat hepatocytes. Because hepatic stellate cells play a pivotal role in liver fibrogenesis, these in vitro findings raise a possibility that LPA and S1P could act as a stimulator of liver fibrosis and an inhibitor of liver regeneration. In evaluating a role in vivo, plasma LPA level was revealed to be increased in patients with chronic hepatitis C in relation to the grade of liver fibrosis and in rats with acute liver injury with toxin or surgery in relation to its severity. Plasma LPA level was also correlated with serum autotaxin activity. Whether the increase of plasma LPA level might be merely a result or a cause of liver fibrosis should be further clarified. On the other hand, in S1P₂-deficient mice the wound healing response of hepatic myofibroblast proliferation to acute liver injury induced by carbon tetrachloride was reduced, suggesting that S1P₂ might trigger hepatic wound healing. Clinical significances of LPA and S1P should be further investigated.