Autophagy activation by Jiang Zhi Granule protects against metabolic stress-induced hepatocyte injury

• Published in: World journal of gastroenterology : WJG 2018-03, Vol.24 (9), p.992-1003
• Main Authors: Zheng, Yi-Yuan, Wang, Miao, Shu, Xiang-Bing, Zheng, Pei-Yong, Ji, Guang
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - drug effects; Basic Study; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - pharmacology; Energy Metabolism - drug effects; Hep G2 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Male; Mice, Inbred C57BL; Microtubule-Associated Proteins - metabolism; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; Oxidative Stress - drug effects; Palmitic Acid - toxicity; Phosphatidylinositol 3-Kinase - metabolism; Reactive Oxygen Species - metabolism; Sequestosome-1 Protein - metabolism; Signal Transduction - drug effects; Time Factors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v24.i9.992

To elucidate the potential role of autophagy and the protective effects of Jiang Zhi Granule (JZG) in metabolic stress-induced hepatocyte injury. An and 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 ( = 10), high fat (HF) group ( = 13) and JZG group ( = 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 , 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.