Published online Mar 7, 2018. doi: 10.3748/wjg.v24.i9.992
Peer-review started: November 10, 2017
First decision: December 13, 2017
Revised: December 22, 2017
Accepted: January 1, 2018
Article in press: January 1, 2018
Published online: March 7, 2018
To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule (JZG) in metabolic stress-induced hepatocyte injury.
An in vitro and in vivo approach was used in this study. HepG2 cells were incubated in culture medium containing palmitate (PA; 0, 0.1, 0.2, 0.3, 0.4 or 0.5 mmol/L) and treated with or without JZG (100 μg/mL) for 24 h or 48 h, and the progression of autophagy was visualized by stable fluorescence-expressing cell lines LC3 and p62. Western blot analyses were performed to examine the expression of LC3-II/LC3-I, p62, mTOR and PI3K, while mitochondrial integrity and oxidative stress were observed by fluorescence staining of JC-1 and reactive oxygen species. C57BL/6 mice were divided into three groups: control group (n = 10), high fat (HF) group (n = 13) and JZG group (n = 13); and, histological staining was carried out to detect inflammation and lipid content in the liver.
The cell trauma induced by PA was aggravated in a dose- and time-dependent manner, and hepatic function was improved by JZG. PA had dual effects on autophagy by activating autophagy induction and blocking autophagic flux. The PI3K-AKT-mTOR signaling pathway and the fusion of isolated hepatic autophagosomes and lysosomes were critically involved in this process. JZG activated autophagy progression by either induction of autophagosomes or co-localization of autophagosomes and lysosomes as well as degradation of autolysosomes to protect against PA-induced hepatocyte injury, and protected mitochondrial integrity against oxidative stress in PA-induced mitochondrial dysfunction. In addition, JZG ameliorated lipid droplets and inflammation induced by HF diet in vivo, leading to improved metabolic disorder and associated liver injury in a mouse model of non-alcoholic fatty liver disease (NAFLD).
Metabolic stress-induced hepatocyte injury exhibited dual effects on autophagy and JZG activated the entire process, resulting in beneficial effects in NAFLD.
Core tip: Non-alcoholic fatty liver disease (NAFLD), which is mainly characterized by the accumulation of lipids and energy metabolism dysfunction, is now one of the most common risk factors worldwide. As studies have demonstrated that autophagy is important in the maintenance of normal hepatocyte function and in the response to pathogenic changes, we examined the potential role of autophagy in metabolic stress-induced hepatocyte injury. The results showed that metabolic stress had dual effects on autophagy, resulting in autophagy induction and autophagic flux inhibition. The Chinese herbal formula Jiang Zhi Granule activated the autophagy process to protect against metabolic stress-induced hepatocyte injury in NAFLD.