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bioRxiv · 10.1101/2022.10.04.510778

Effects of protoscoleces excretory-secretory products of Echinococcus granulosus on hepatocyte growth, function, and glucose metabolism

Luo, G.·Li, H.·Lu, Q.·Cao, J.·Lv, H.·Jiang, Y.
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Abstract

Cystic echinococcosis (CE) is one of the most widespread and harmful zoonotic parasitic diseases and it most commonly affects the liver. In this study, we characterized multiple changes in mouse hepatocytes following treatment with excretory-secretory (ES) products of Echinococcus granulosus protoscoleces by a factorial experiment. The cell counting kit-8 assay (CCK-8), the 5-ethynyl-2-deoxyuridine (EdU) assay, and flow cytometry were used to detect the growth of hepatocytes. Inverted microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were used to observe the morphology and ultrastructure of hepatocytes. An automatic biochemical analyzer and an ELISA detection kit were used to determine six conventional hepatocyte enzymatic indices, the levels of five hepatocyte-synthesized substances, and the contents of glucose and lactate. Western blot analysis was conducted to analyze the protein expression of six rate-limiting enzymes in the glucose metabolism pathway in hepatocytes: glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), and leucine arylamidase (LAP). The results of the CCK-8 and EdU assays both showed that ES could inhibit the proliferation of hepatocytes, and flow cytometry indicated that ES could promote apoptosis of hepatocytes. After ES treatment, the ultrastructure of hepatocytes was disrupted to a certain extent. The changes in the cell membrane and microvilli were observed through SEM, and the changes in the nucleus, mitochondria, and rough endoplasmic reticulum were observed through TEM. After ES treatment, the enzymatic activities of the six hepatocyte enzymes were increased in addition to the Fe metabolism and the synthesis of albumin (ALB), uric acid (UA), and urea, whereas the synthesis of transferrin (TRF) was decreased. The expression levels of all six key enzymes in the glucose metabolism pathway in hepatocytes were decreased, and the biological effects were significantly inhibited. We analyzed the causes and possible complications caused by various changes and advocate corresponding measures. We also propose possible mechanisms by which protoscoleces cause hepatocyte necrosis, but the specific mechanism requires further study. Author SummaryEchinococcus granulosus, the most widely distributed and most infected tapeworm, has caused serious economic and social burdens to pastoral areas in China. The metacestodes of Echinococcus granulosus mainly infect the liver of intermediate hosts (humans, cattle, sheep, etc.). Currently, the effects of Echinococcus granulosus on hepatocytes ultrastructure, enzymology, function, and glucose metabolism have not been characterized, and accurate characterization is crucial in the study of related pathogenesis and preventive therapy. Here, we characterize multiple changes in hepatocytes using excretory-secretory (ES) products of Echinococcus granulosus protoscoleces and mouse hepatocyte action by a factorial experiment. We found that ES inhibited hepatocyte proliferation and promoted hepatocyte apoptosis. ES can cause a certain degree of damage to the cell membrane, nucleus, mitochondria, and endoplasmic reticulum of hepatocytes. After ES treatment, six enzymatic indexes of hepatocytes were elevated, they were ALT, AST, LDH, ALP, GGT, and LAP, and Fe, ALB, UA, and urea levels synthesized by hepatocytes were significantly higher and TRF levels were significantly lower. Reduced expression of rate-limiting enzymes in six pathways of glucose metabolism in hepatocytes, including PFK-1, IDH, G-6-PD, GS, GP, and GLUT-2, indicating that ES inhibits glucose metabolism in hepatocytes. Our study not only characterized the effects of ES on hepatocytes in detail but also proposed the possible mechanisms causing these effects, which provided a basis for subsequent studies on related pathogenesis and prevention, and treatment.

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Luo, G., Li, H., Lu, Q., Cao, J., Lv, H., Jiang, Y.. 2022-10-04. Effects of protoscoleces excretory-secretory products of Echinococcus granulosus on hepatocyte growth, function, and glucose metabolism. https://doi.org/10.1101/2022.10.04.510778

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