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  • br Increased blood ATX and LPA in liver

    2024-02-19


    Increased blood ATX and LPA in liver fibrosis Although previous in vitro findings have suggested a link between LPA and liver fibrosis in vivo, whether LPA plays a primary role in the pathogenesis of liver fibrosis has remained uncertain. No phenotypic changes in livers of LPA receptor-deficient mice have been demonstrated [25]. No modulations in liver fibrosis have so far been reported in these mice after liver injury. Of note, previous evidence has demonstrated relatively low gene GF 109203X of LPA receptors in liver [26], suggesting that the roles of LPA may be limited in liver fibrosis. In contrast, LPA receptor-deficient mice were markedly protected from bleomycin-induced pulmonary fibrosis [27]. However, experiments to clarify the significance of ATX and LPA in liver fibrosis found plasma LPA and serum ATX activity increased in patients with chronic hepatitis C. A strong correlation was observed between plasma LPA and serum ATX activity. Furthermore, plasma LPA and serum ATX activity were correlated with blood markers for liver fibrosis, such as serum hyaluronate and platelet counts [11]. Plasma LPA and serum ATX activity increased in association with liver fibrosis stage histologically in these patients. An association between liver fibrosis and plasma LPA and serum ATX activity has been further confirmed in experimental rat models [12]. In this study, plasma LPA and serum ATX activity were correlated to the extent of liver fibrosis induced by carbon tetrachloride [12]. What mechanism responsible for increased plasma LPA and serum ATX activity in liver fibrosis? Factors involved with increasing serum ATX activity are likely primary because plasma LPA is essentially regulated by ATX [11], [12]. To explain increased serum ATX activity, two possibilities should be considered (although the origin and fate of serum ATX have not been fully elucidated): increased ATX production as a result of liver fibrosis or reduction in ATX clearance. In carbon tetrachloride-induced fibrotic rat livers, ATX mRNA expression was unaltered [12], ie, production was not increased. Increased serum ATX activity was observed in 70% hepatectomized rats as early as three hours post-surgery and maintained for 24h [12]. These findings suggest that increased serum ATX activity may be caused by a reduction in clearance. As such, the liver may not be the major site of ATX production, but the site of ATX clearance. In agreement, ATX was subsequently shown to be cleared from the circulation within minutes, taken up, and degraded in liver sinusoidal endothelial cells [28]. During the process of liver fibrosis, liver sinusoidal endothelial cells are known to undergo phenotypic changes with a loss of various receptors and sinusoidal endothelial fenestrae causing the capillarization of the sinusoids, thereby impairing the uptake of various substances [29]. Thus, the phenotypic changes in liver sinusoidal endothelial cells during liver fibrosis may lead to reduced ATX clearance thereby increasing circulating ATX activity and LPA concentration (Fig. 1). Hyaluronate, an established blood marker for liver fibrosis, is removed from the circulation by liver sinusoidal endothelial cells and its uptake is reduced by the phenotypic changes that occur in these cells during fibrosis [30].
    ATX as potential serum marker for liver fibrosis As described earlier, liver fibrosis occurs in response to chronic liver injury and may ultimately lead to cirrhosis, with portal hypertension, hepatocellular carcinoma, and liver failure as possible consequences. A percutaneous liver biopsy has long remained the gold standard for the staging of fibrosis. However, a noninvasive, reproducible method of assessing fibrosis is needed to monitor disease progression, clinical outcomes, and the response to treatment, since liver fibrosis is now known to be a dynamic process with significant potential for reversal. Furthermore, the limitations of needle liver biopsies with respect to sampling errors and interobserver variations have been well recognized, highlighting the need for further diagnostic strategies [31].