Metabolomics-based elucidation of the regional difference mechanism of the PPARγ signaling axis in sheep hepatic cystic echinococcosis.

Abstract

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with Echinococcus granulosus sensu lato, with the liver being the primary affected organ. This study aimed to investigate the metabolic profile alterations and differential regulation of the PPARγ signaling axis in proximal and distal hepatic tissues following E. granulosus(s.l.) infection in sheep, thereby elucidating the molecular mechanisms underlying local lipid metabolic reprogramming. Naturally E. granulosus(s.l.) infected sheep livers were used as subjects, with cyst-adjacent Close liver tissue (CLT), Distal liver tissue (DLT), and uninfected liver tissue (NC) collected as controls. Untargeted metabolomics combined with KEGG enrichment analysis was employed to compare metabolic profiles among the three groups; GSEA enrichment analysis was performed to assess changes in lipid metabolism-related pathways; qPCR and Western blot were used to detect mRNA and protein expression levels of PPARγ, SREBP-1c, ACC1, and CD36; HE staining was conducted to observe the degree of inflammatory infiltration. Metabolomic analysis revealed that, compared with the NC group, the CLT group exhibited suppressed TCA cycle activity, amino acid metabolism disorders, and purine metabolism abnormalities, whereas these disturbances were markedly attenuated in the DLT group. KEGG and GSEA enrichment analyses further demonstrated that the PPAR signaling pathway, steroid hormone biosynthesis, and arachidonic acid metabolism were significantly downregulated in the CLT group, with alterations in glycerophospholipid metabolism also observed. At the molecular level, mRNA and protein expression levels of PPARγ, SREBP-1c, ACC1, and CD36 in the CLT group were significantly lower than those in the NC group, while these parameters showed substantial recovery in the DLT group. HE staining indicated that the degree of inflammatory infiltration in the CLT group was significantly higher than that in the DLT group. E. granulosus(s.l.) infection can suppress the PPARγ signaling axis in proximal hepatic tissues of sheep, leading to lipid metabolic reprogramming and exacerbated inflammation, whereas distal tissues can maintain metabolic homeostasis through compensatory mechanisms. Purine metabolism disorders may attenuate PPARγ and downstream gene expression by regulating AMPK signaling, providing novel therapeutic targets for metabolic intervention in CE-associated liver injury.