Limonin Attenuates LPS-Induced Hepatotoxicity by Inhibiting Pyroptosis via NLRP3/Gasdermin D Signaling Pathway.

Abstract

Lipopolysaccharide (LPS)-induced liver injury is the main factor in acute liver failure. The current study aims to investigate the protection of limonin, an antioxidant compound from citrus fruit, against LPS-induced liver toxicity and elucidate the potential mechanisms. We found that limonin elevated cell viability and reduced LDH release in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis by inhibiting membrane rupture, reducing ROS generation, and decreasing gasdermin D activation. Moreover, limonin inhibited the formation of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like protein containing a CARD (ASC) complex by reducing the related protein expression and the colocalization cytosolic of NLRP3 and caspase-1 and then suppressed IL-1β maturation. Ultimately, we established LPS-induced hepatotoxicity in vivo by using C57BL/6 mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50 and 100 mg/kg) orally. We found that limonin dereased the serum ALT and AST activity and LDH release and increased the hepatic GSH amount in LPS-treated mice. Additionally, the liver histological evaluation revealed that limonin protects against LPS-induced liver damage. We further demonstrated that limonin ameliorated LPS-induced hepatotoxicity by inhibiting pyroptosis via the NLRP3/gasdermin D signaling pathway. In summary, this study uncovered the mechanism whereby limonin mitigated LPS-induced hepatotoxicity and documented that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.

• Authors: Runyu Yang, Hanxi Yu, Jiaxi Chen, Jianwei Zhu, Changqin Song, Lvqi Zhou, Yang Sun, Qi Zhang
• Journal: Journal of agricultural and food chemistry (J Agric Food Chem) Vol. 69 Issue 3 Pg. 982-991 (Jan 27 2021) ISSN: 1520-5118 [Electronic] United States
• PMID: 33427450 (Publication Type: Journal Article)

Chemical References

• Gsdmd protein, mouse
• Intracellular Signaling Peptides and Proteins
• Limonins
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Phosphate-Binding Proteins
• Caspase 1
• limonin

Topics

• Animals
• Caspase 1 (genetics, metabolism)
• Chemical and Drug Induced Liver Injury (drug therapy, etiology, metabolism, physiopathology)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Limonins
• Lipopolysaccharides (adverse effects)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Phosphate-Binding Proteins (genetics, metabolism)
• Pyroptosis (drug effects)