Genipin alleviates sepsis‐induced liver injury by restoring autophagy

• Published in: British journal of pharmacology 2016-03, Vol.173 (6), p.980-991
• Main Authors: Cho, Hong‐Ik, Kim, So‐Jin, Choi, Joo‐Wan, Lee, Sun‐Mee
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - blood; Animals; Aspartate Aminotransferases - blood; Autophagy; Autophagy - drug effects; Autophagy-Related Proteins - metabolism; Calpain; Chemical compounds; Chloroquine; Chloroquine - pharmacology; Cytokines; Fluctuations; Gardenia; Genipin; Inflammation; Interleukin-6 - blood; Iridoids - pharmacology; Iridoids - therapeutic use; Liver; Liver - drug effects; Liver - metabolism; Liver - ultrastructure; Liver Diseases - blood; Liver Diseases - drug therapy; Liver Diseases - metabolism; Male; Membrane proteins; Mice; Mice, Inbred ICR; Microscopy, Electron, Transmission; p62 Protein; Phagocytosis; Protective Agents - pharmacology; Protective Agents - therapeutic use; Proteins; Research Paper; Research Papers; Sepsis; Sepsis - blood; Sepsis - complications; Sepsis - drug therapy; Sepsis - metabolism; Serum levels; Signal transduction; Tumor Necrosis Factor-alpha - blood
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13397

Background and Purpose Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli including inflammation and microbial infection. Genipin, an aglycon of geniposide found in gardenia fruit, is well known to have anti‐inflammatory, antibacterial and antioxidative properties. This study examined the protective mechanisms of genipin against sepsis, with particular focus on the autophagic signalling pathway. Experimental Approach Mice were subjected to sepsis by caecal ligation and puncture (CLP). Genipin (1, 2.5 and 5 mg·kg−1) or vehicle (saline) was injected i.v. immediately (0 h) after CLP, and chloroquine (60 mg·kg−1), an autophagy inhibitor, was injected i.p. 1 h before CLP. Blood and liver tissues were isolated 6 h after CLP. Key Results Genipin improved survival rate and decreased serum levels of aminotransferases and pro‐inflammatory cytokines after CLP; effects abolished by chloroquine. The liver expression of autophagy‐related protein (Atg)12‐Atg5 conjugate increased after CLP, and this increase was enhanced by genipin. CLP decreased Atg3 protein liver expression, and genipin attenuated this decrease. CLP impaired autophagic flux, as indicated by increased liver expression of microtubule‐associated protein‐1 light chain 3‐II and sequestosome‐1/p62 protein; this impaired autophagic flux was restored by genipin, and chloroquine abolished this effect. Genipin also attenuated the decreased expression of lysosome‐associated membrane protein‐2 and Rab7 protein and increased expression of calpain 1 protein induced by CLP in the liver. Conclusions and Implications Our findings suggest that genipin protects against septic injury by restoring impaired autophagic flux. Therefore, genipin might be a potential therapeutic agent for the treatment of sepsis.