Role of autotaxin for the pathogenesis of liver fibrosis in biliary atresia

Abstract

Biliary atresia (BA) is one of the most common causes of neonatal cholestasia. The etiology of BA remains mysterious. Lack of reliable noninvasive diagnostic biomarkers of BA may leads to delayed diagnosis and worse patient outcome. Hence, the identification of noninvasive biomarkers to assess liver fibrosis is desirable. The main aim of this study was to explore various contributors for hepatic dysfunction including autotaxin (ATX), relative telomere length (RLT), global DNA methylation and oxidative stress whether these biomarkers could be related to the pathogenesis of liver fibrosis in BA. One hundred and fourteen post operative BA patients and 114 age-matched healthy controls were enrolled. We found that BA patients had higher circulating ATX and liver stiffness than controls. Our findings showed that elevated circulating ATX was associated with status of jaundice, hepatic dysfunction, and liver stiffness in postoperative BA. In addition, the current study provides evidences for up-regulation of ATX mRNA expression in liver specimens of BA patients compared to those in controls. The up-regulation of ATX expression in BA liver samples was performed with immunohischemical detection of ATX antigens within the liver bile duct epithelia and the hepatocytes. ATX mRNA expression was also significantly elevated and correlated with a decrease in ATX promoter methylation in BA patients compared to the controls. Moreover, this study supports the association between RTL in peripheral blood leukocytes and higher risk of liver fibrosis in BA. RLT in blood leukocytes was also associated with disease severity, showing that BA patients with advanced-stage exhibited excessive telomere shortening. Additionally, this study reported that, independent of risk factors, hypomethylation of retrotransposable DNA elements (Alu and LINE-1) was associated with shorter telomeres, elevated oxidative DNA damage, and a higher risk of liver fibrosis in BA. Based on the aforementioned findings, combinations of circulating ATX levels, hepatic ATX expression, relative telomere length, global DNA methylation, and oxidative DNA damage could serve as possible noninvasive biomarkers reflecting the disease severity and the development of liver fibrosis in the post Kasai BA patients. Autotaxin could play a crucial role in the pathogenesis of liver fibrosis in chornic liver disease including biliary atresia.