BRL 37344, sodium salt br Conclusion br Acknowledgments This

Conclusion
Acknowledgments This research has been supported by the Ratchadaphiseksomphot Endowment Fund 2013 of Chulalongkorn University (CU-56-341-AS) and the Ratchadapiseksompotch Fund (RA55/22), Faculty of Medicine, Chulalongkorn University. The authors commemorate the 100th Anniversary of the King Chulalongkorn Memorial Hospital. The authors would like to thank Dr. Pongsak Yuktanandana and Dr. Aree Tanavalee for sample collection. We gratefully acknowledge Research Core Facility of the Department of Biochemistry and ChulaMRC (Chulalongkorn Medical Research Center) for providing facilities.
Autotaxin lysophospholipase D activity and lysophosphatidic BRL 37344, sodium salt production Lysophosphatidic acid (1- or 2-acyl-lysophosphatidic acid; LPA) elicits a wide variety of biological responses including cell migration, neurogenesis, angiogenesis, smooth-muscle contraction, platelet aggregation, and wound healing [1], [2]. Because it is present in blood at a concentration of ~0.1μmol/L [3], ie, close to the concentration that exerts various effects on cells in vitro[1], [2], LPA is regarded as a circulatory paracrine mediator. A major portion of LPA in blood is generated by lysophospholipase D (lysoPLD) from lysophospholipids, mainly lysophosphatidylcholine [4]. When cloned, lysoPLD was unexpectedly found to be identical to autotaxin (ATX). ATX was originally discovered in conditioned medium from A2058 human melanoma cell cultures and was characterized as a stimulator of cell migration [5]. Since then, ATX has been speculated to play a role in cancer invasion or metastasis as an autocrine motility factor [6]. However, the exact pathophysiological significance of ATX remained unknown until the discovery of its lysoPLD activity [7], [8]. ATX is responsible for the hydrolysis of lysophospholipids (mainly lysophosphatidylcholine), producing LPA in blood (Fig. 1). In heterozygous ATX-null mice, LPA plasma concentration was one-half that in wild-types [9], [10]. A strong correlation between serum ATX activity and plasma LPA has also been observed in humans [11] and rats [12]. Homozygous ATX-null mice were embryonically lethal [9]. Collectively, these results suggest that the pathophysiologic functions of ATX can largely be attributed to its ability to produce LPA.
LPA stimulates hepatic stellate cell proliferation and contraction and inhibits apoptosis Irrespective of cellular insult, ie, viral infection, alcohol or drug abuse, a wound healing response generally occurs in injured liver tissue. The persistence of this response may result in liver fibrosis. Among liver cells, hepatic stellate cells are known to play a major role in the fibrotic process in which they undergo a phenotypic change to myofibroblasts [13], [14], [15]. This activation ultimately results in proliferation, production of abundant extracellular matrices, increased contractility and motility. The process of liver fibrosis now appears to be reversible in rats [16] and humans [17], and hepatic stellate cell apoptosis may be a key event in this reversal, since the mechanisms responsible for the spontaneous resolution of rat liver fibrosis involve hepatic stellate cell apoptosis [18], [19], and the direct induction of hepatic stellate cell apoptosis has reduced experimental liver fibrosis in rats [20]. Thus, many factors with potentially fibrogenic activities in the liver have been evaluated in light of their effects on hepatic stellate cell activation and apoptosis [15]. Regarding its potential effect on hepatic stellate cells, LPA was first shown to stimulate rat hepatic stellate cell proliferation in a pertussis toxin-sensitive manner, suggesting that LPA could be a pro-fibrogenic factor in liver [21]. Because hepatic stellate cells reside around the hepatic sinusoid, a unique vasculature in liver, the contraction of these cells results in increased pressure in the hepatic sinusoid and hence the portal vein. Thus, hepatic stellate cells appear to play a direct role in pathogenesis of portal hypertension, a major complication associated with liver fibrosis. In this context, LPA was further shown to enhance the contractility of hepatic stellate cells in vitro through Rho/Rho kinase activation [22], [23], suggesting that LPA might be involved in the pathogenesis of portal hypertension. Furthermore, LPA was shown to inhibit hepatic stellate cell apoptosis in vitro through Rho/Rho kinase activation [24]. Collectively, these in vitro findings suggest that LPA may be a pro-fibrogenic factor in the liver (Fig. 2).