Afzelin ameliorates D‐galactosamine and lipopolysaccharide‐induced fulminant hepatic failure by modulating mitochondrial quality control and dynamics

Background and Purpose Fulminant hepatic failure (FHF) is a fatal clinical syndrome that results in excessive inflammation and hepatocyte death. Mitochondrial dysfunction is considered to be a possible mechanism of FHF. Afzelin, a flavonol glycoside found in Houttuynia cordata Thunberg, has anti‐inf...

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Bibliographic Details
Published in:British journal of pharmacology 2017-01, Vol.174 (2), p.195-209
Main Authors: Lee, Sang‐Bin, Kang, Jung‐Woo, Kim, So‐Jin, Ahn, Jongmin, Kim, Jinwoong, Lee, Sun‐Mee
Format: Article
Language:English
Subjects:
Alanine
Alanine transaminase
Animals
Antioxidants
Biosynthesis
Cytokines
D-Galactosamine
Dose-Response Relationship, Drug
Dynamin
Fusion protein
Galactosamine
Glutamate dehydrogenase
Inflammation
Lipopolysaccharides
Liver
Liver Failure, Acute - chemically induced
Liver Failure, Acute - drug therapy
Liver Failure, Acute - pathology
Male
Mannosides - pharmacology
Mice
Mice, Inbred ICR
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - pathology
Parkin protein
Peroxisome proliferator-activated receptors
Proanthocyanidins - pharmacology
Proteins
PTEN protein
Quality control
Research Paper
Research Papers
Rodents
Serum levels
Structure-Activity Relationship
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Summary:Background and Purpose Fulminant hepatic failure (FHF) is a fatal clinical syndrome that results in excessive inflammation and hepatocyte death. Mitochondrial dysfunction is considered to be a possible mechanism of FHF. Afzelin, a flavonol glycoside found in Houttuynia cordata Thunberg, has anti‐inflammatory and antioxidant properties. The present study elucidated the cytoprotective mechanisms of afzelin against D‐galactosamine (GalN)/LPS induced FHF, particularly focusing on mitochondrial quality control and dynamics. Experimental Approach Mice were administered afzelin i.p. 1 h before receiving GalN (800 mg·kg−1)/LPS (40 μg·kg−1), and they were then killed 5 h after GalN/LPS treatment. Key Results Afzelin improved the survival rate and reduced the serum levels of alanine aminotransferase and pro‐inflammatory cytokines in GalN/LPS‐treated mice. Afzelin attenuated the mitochondrial damage, as indicated by diminished mitochondrial swelling and mitochondrial glutamate dehydrogenase activity in GalN/LPS‐treated mice. Afzelin enhanced mitochondrial biogenesis, as indicated by increased levels of PPAR‐γ coactivator 1α, nuclear respiratory factor 1 and mitochondrial transcription factor A. Afzelin also decreased the level of mitophagy‐related proteins, parkin and PTEN‐induced putative kinase 1. Furthermore, while GalN/LPS significantly increased the level of fission‐related protein, dynamin‐related protein 1, and decreased the level of fusion‐related protein, mitofusin 2; these effects were attenuated by afzelin. Conclusions and Implications Our findings demonstrated that afzelin protects against GalN/LPS‐induced liver injury by enhancing mitochondrial biogenesis, suppressing excessive mitophagy and balancing mitochondrial dynamics.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.13669