Clonorchis sinensis infection induces hepatobiliary injury via disturbing sphingolipid metabolism and activating sphingosine 1-phosphate receptor 2

Abstract

Clonorchis sinensis (C. sinensis) infection induces severe hepatobiliary injuries, which can cause inflammation, periductal fibrosis, and even cholangiocarcinoma. Sphingolipid metabolic pathways responsible for the generation of sphingosine-1-phosphate (S1P) and its receptor S1P receptors (S1PRs) have been implicated in many liver-related diseases. However, the role of S1PRs in C. sinensis-mediated biliary epithelial cells (BECs) proliferation and hepatobiliary injury has not been elucidated. In the present study, we found that C. sinensis infection resulted in alteration of bioactive lipids and sphingolipid metabolic pathways in mice liver. Furthermore, S1PR2 was predominantly activated among these S1PRs in BECs both in vivo and in vitro. Using JTE-013, a specific antagonist of S1PR2, we found that the hepatobiliary pathological injuries, inflammation, bile duct hyperplasia, and periductal fibrosis can be significantly inhibited in C. sinensis-infected mice. In addition, both C. sinensis excretory-secretory products (CsESPs)- and S1P-induced activation of AKT and ERK1/2 were inhibited by JTE-013 in BECs. Therefore, the sphingolipid metabolism pathway and S1PR2 play an important role, and may serve as potential therapeutic targets in hepatobiliary injury caused by C. sinensis-infection.

Immunomodulatory effects of albendazole, trichlorobendazole and wortmannilactone F on Clonorchis sinensis infection

“…CK-19 keratin has been shown to be a marker for the diagnosis and identi cation of hepatocellular carcinoma cells [30]. Recent evidence pinpoints that Clonorchis sinensis infection could lead to the increased expression of CK-19 in hepatocyte and hepatobiliary tissues [8,41]. In agreement with these report, we also demonstrated that the expression level of CK-19 keratin in hepatic tissue was elevated in rat with chronic Clonorchis sinensis infection.…”

Clonorchis sinensis infection amplifies hepatocellular carcinoma stemness, predicting unfavorable prognosis

“…sinensis is a prominent food-borne parasite prevalent in regions such as China, particularly in Guangxi, Guangdong, Heilongjiang and Liaoning [ 12 , 29 ]. This parasite has been associated with various hepatobiliary system injuries, encompassing inflammation, periductal fibrosis, cholangiocarcinoma, and even HCC [ 20 , 30 ]. While a substantial body of evidence links clonorchiasis to cholangiocarcinoma [ 18 , 31 , 32 ], the connection between clonorchiasis and HCC is less acknowledged.…”

“…Furthermore, epidemiological and clinical studies have unveiled disconcerting links between C. sinensis infection and the prognosis of HCC patients, suggesting that it may serve as a substantial risk factor for HCC [10]. The carcinogenesis of C. sinensis infection involves various factors, such as mechanical obstruction and damage to the biliary barrier system, consisting of infectionrelated inflammation, pathological effects from excretory-secretory products (ESPs), enhanced features of epithelial-mesenchymal transition, and immunopathology imbalance [10,[19][20][21]. However, the intricate mechanisms underlying C. sinensis's contribution to HCC development remain incompletely elucidated.…”

Clonorchis sinensis: a mimic of hepatic mucinous cystic neoplasm or just a fluke?

“…Trauma to biliary epithelium causes ulceration and desquamation, and results in typical pathological findings of periductal fibrosis, epithelial hyperplasia and glandular metaplasia. 6 Chronic infection can lead to clinical manifestations beyond acute phase infection such as biliary obstruction, stone formation, cholecystitis, cholangitis, hepatitis, and cirrhosis. 7 Structural changes include hepatomegaly, biliary ductal dilatation, and stricture formation.…”