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  • P-III-1050

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

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Human Health Insights (Neurobiology, Cardiovascular, Liver, Kidney etc.)

Poster

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

Thema

  • Human Health Insights (Neurobiology, Cardiovascular, Liver, Kidney etc.)

Mitwirkende

Thibaut Léger (Fougères / FR), Sarah Alilat (Fougères / FR), Pierre-Jean Ferron (Rennes / FR), Léonie Dec (Fougères / FR), Tahar Bouceba (Paris / FR), Rachelle Lanceleur (Fougères / FR), Sylvie Huet (Fougères / FR), Yoann Devriendt-Renault (Maisons-Alfort / FR), Julien Parinet (Maisons-Alfort / FR), Bruno Clément (Rennes / FR), Valérie Fessard (Fougères / FR), Ludovic Le Hégarat (Fougères / FR)

Abstract

Background and aims: Chlordecone (CLD) is a pesticide used in the French West Indies (FWI) until the 1990s. Despite its ban, CLD persists in soils and contaminates food webs. In 2014, CLD was detected in 92 to 95% in the human population of the FWI. In humans, CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH) and glucuronide conjugates. As it is thought to be involved in hepatic fibrosis and cancer besides other pathologies, it is a major public health concern. The aim of this study was to compare the fate and mechanistic effects of CLD and CLDOH in hepatotoxicity as well as their impact on metabolic dysfunction-associated steatotic liver disease (MASLD) susceptibility using in vitro liver cell models.

Methods: A concentration-response and a kinetic study were performed in human HepaRG cells to investigate the impact of CLD and CLDOH on liver response using metabolomics and proteomics. The responses of HepaRG cells were compared with those obtained in primary human hepatocyte (PHH) cultures. Docking experiments, surface plasmon resonance (SPR), and high-content screening were used to confirm some specific effects. A 3D-cell model of MASLD was also used to investigate whether CLD and CLDOH can affect the MASLD process.

Results: Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively and quickly metabolized into a glucuronide conjugate, whereas CLD was mainly sequestered in liver cells. CLD and CLDOH impacted OXPHOS and slightly decreased ATP levels after a few hours of exposure but they were restored at 24 hours. CLD but not CLDOH induced a drastic depletion of Septin-2, -7, -9, -10, and -11 due to proteasomal degradation. SPR experiments indicated that CLD and CLDOH could bind to Septin-2. CLD disrupted liquid droplet (LD) location and increased saturated long-chain dicarboxylic acid (DCA) production and secretion by inhibiting fatty acid oxidation (FAO) and stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in a 3D co-culture model of MASLD.

Conclusions: CLD hepatoxicity is specifically driven by the degradation of septins, involved in liver steatosis, fibrosis and cancer. In contrast, its major metabolite, CLDOH, was too rapidly metabolized to induce septin degradation. Septin depletion impacted LDs, resulting in the inhibition of mitochondrial β-oxidation favoring ω-oxidation and the production of saturated long-chain DCAs. These effects, associated with the perturbation of bile acid (BA) secretion, induced hepatotoxicity and susceptibility to fibrosis.

Impact and implications: The mechanisms involved in CLD hepatotoxicity via its interaction with septins were deciphered. The conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. These results suggest that protective strategies could be explored to reduce the hepatotoxicity of CLD.

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