Inhibition of hepatic UGT1A1 attenuates bilirubin metabolism and aggravates liver fibrosis in schistosomiasis through the NF-κB signaling pathway

Abstract

AbstractBackground:Hepatic fibrosis is an important clinical manifestation of chronic schistosome infection. Patients with advanced schistosomiasis show varying degrees of abnormalities in liver fibrosis indicators and bilirubin metabolism. However, the molecular mechanism underlying the bilirubin metabolism abnormalities caused bySchistosoma japonicuminfection remained unclear. Meanwhile, the role of bilirubin in our body is controversial, and the interaction between bilirubin and hepatocytes remains to be further studied.Methods:Blood samples from advanced schistosomiasis patients in Jiangsu province were collected for clinical blood biochemical examination according to standard procedures, and descriptive analysis and correlation analysis were performed for bilirubin and liver injury-related indicators. The mechanisms of bilirubin metabolic changes were explored by establishing a mouse model ofSchistosoma japonicuminfection combined with experiments of in vitro and spatial metabolomics techniques. Bilirubin regulation of hepatic fibrosis-related signaling pathways was further investigated in vitro.Results:Abnormal bilirubin metabolism was found in 23.35% of advanced schistosomiasis patients in Jiangsu Province. In the infection mouse model, liver fibrosis increased with infection time, whereas liver UGT1A1 showed continual low expression and an associated with impaired bilirubin metabolism in mice. Meanwhile, we found that uridine, a key substance associated with bilirubin metabolism in schistosome infection, was identified through spatial metabolomics techniques. In vitro experiments suggested that soluble egg antigen may be a key inhibitor of hepatic UGT1A1 expression after schistosome infection. In addition, the relationship between the abnormal increases in bilirubin and hepatic fibrosis in patients with schistosomiasis was unclear. We observed a positive correlation between abnormal bilirubin metabolism and abnormalities in ALT, AST, LN, and CIV in patients with advanced schistosomiasis. Moreover, high concentrations of bilirubin activated the NF-κB signaling pathway in L-O2 hepatocytes in vitro.Conclusions:The impaired bilirubin metabolism due to low expression of UGT1A1 caused bySchistosoma japonicuminfection may play an important role in schistosomiasis liver fibrosis through the NF-κB signaling pathway.