Abstract
BackgroundNon-alcoholic fatty liver disease (NAFLD) may increase the sensitivity to liver injury caused by stimulants such as drugs and poisons. The traditional Chinese medicine (TCM) Jiang-Zhi Granule (JZG) has been proven effective for improving liver function, reducing hepatic fat accumulation and inflammation in NAFLD. The purpose of this study is to evaluate the effect of JZG on the susceptibility of NAFLD rats to liver injury and to identify the relevant mechanism.MethodsForty wistar rats were randomly divided into five groups, normal group, normal+CCl4 group, high-fat diet (HFD) group, HFD + CCl4 group, and HFD + CCl4 + JZG group. NAFLD were established with HFD for 8 weeks. Then Low-dose CCl4 was given intraperitoneally to induce liver injury in NAFLD rats for 48 h. From the 5th week of HFD, intragastric administration of JZG was simultaneously given to the rats in the HFD + CCl4 + JZG group. At the end of the experiment, liver histological pathology, serum transaminase, lipid in liver and blood, as well as hepatic expression levels of endoplasmic reticulum stress (ERS) related molecules were evaluated.ResultsNAFLD rat model was established by eight-week HFD feeding, exhibiting elevated levels of hepatic lipid, blood lipid, serum transaminase and significantly increased expression of ERS related molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (EIF2α), and nuclear factor-kappa B (NFκB) in liver tissues. After injection of CCl4 in NAFLD rats, elevated serum transaminases, severe inflammation and focal necrosis were observed in liver tissue, but no obvious change was found in the rats of normal group. JZG reduced hepatic inflammation, hepatic necrosis, hepatic lipid, blood transaminases and blood lipids in HFD + CCl4 rats. ERS related molecules were significantly elevated by low-dose CCl4 in NAFLD rats, and were down-regulated by JZG.ConclusionThe sensitivity to CCl4-induced liver injury is increased in NAFLD rats, which could be improved by JZG. The pharmacological mechanism may involve the regulation of ERS signaling pathway by JZG.
Highlights
Non-alcoholic fatty liver disease (NAFLD) may increase the sensitivity to liver injury caused by stimulants such as drugs and poisons
Effect of Jiang-Zhi Granule (JZG) on histopathology of liver tissue HE staining (Fig. 1) showed, the rat liver tissue of normal group was structurally complete without abnormal histological structure (Fig. 1a), while different-size lipid droplets were accumulated in hepatocytes of high-fat diet (HFD) rats (Fig. 1c)
Liver injury was more severe in HFD + CCl4 group (Fig. 1d) than HFD group, with infiltration of inflammatory cells and vacuolar degeneration around central vein as well as obvious localized focal necrosis besides severe steatosis
Summary
Non-alcoholic fatty liver disease (NAFLD) may increase the sensitivity to liver injury caused by stimulants such as drugs and poisons. The purpose of this study is to evaluate the effect of JZG on the susceptibility of NAFLD rats to liver injury and to identify the relevant mechanism. Along with the global prevalence of obesity and diabetes, the incidence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. The prevalence of non-alcoholic steatohepatitis (NASH) in NAFLD patients who had liver biopsy with a specific “clinical indication” is estimated to be 59.10% (95% CI, 47.55–69.73). Patients with NAFLD have a higher mortality rate and risk of developing cardiovascular disease or metabolic syndrome related tumors [4, 5]
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