Chlordecone-induced hepatotoxicity and fibrosis are mediated by the proteasomal degradation of septins - Anses - Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail Accéder directement au contenu
Article Dans Une Revue Journal of Hazardous Materials Année : 2024

Chlordecone-induced hepatotoxicity and fibrosis are mediated by the proteasomal degradation of septins

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Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH). In vitro liver cell models were used to investigate the fate and mechanistic effects of CLD and CLDOH using multiomics. A 3D-cell model was used to investigate whether CLD and CLDOH can affect susceptibility to the metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively metabolized into a glucuronide conjugate, whereas CLD was sequestered. CLD but not CLDOH induced a depletion of Septin-2,− 7,− 9,− 10,− 11 due to proteasomal degradation. Septin binding with CLD and CLDOH was confirmed by surface plasmon resonance. CLD disrupted lipid droplet size and increased saturated long-chain dicarboxylic acid production by inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in the 3D model of MASLD. To conclude, CLD hepatoxicity is specifically driven by the degradation of septins. CLDOH, was too rapidly metabolized to induce septin degradation. We show that the conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. This suggests that protective strategies could be explored to reduce the hepatotoxicity of CLD.
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anses-04661415 , version 1 (24-07-2024)

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Thibaut Léger, Sarah Alilat, Pierre-Jean Ferron, Léonie Dec, Tahar Bouceba, et al.. Chlordecone-induced hepatotoxicity and fibrosis are mediated by the proteasomal degradation of septins. Journal of Hazardous Materials, 2024, 476, pp.135177. ⟨10.1016/j.jhazmat.2024.135177⟩. ⟨anses-04661415⟩
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