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

作者：Lee Sang Bin; Kang Jung Woo; Kim So Jin; Ahn Jongmin; Kim Jinwoong; Lee Sun Mee

来源：British Journal of Pharmacology, 2017, 174(2): 195-209.

DOI：10.1111/bph.13669

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 cytoprotectivemechanisms 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 center dot kg(-1))/LPS (40 mu g center dot 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-gamma coactivator 1 alpha, 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.

• 出版日期2017-1