Protective Mechanisms of Garlic and Wolfberry Derivatives on Acute and Chronic Liver Injury Animal Models

This dissertation, "Protective Mechanisms of Garlic and Wolfberry Derivatives on Acute and Chronic Liver Injury Animal Models" by Jia, Xiao, 肖佳, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Liver is one of the most important organs in the body that maintains the homeostasis of metabolism, immunity, detoxification and hematopoiesis. A large number of acute and chronic intoxications and diseases can influence the normal functions of the liver, leading to irreversible liver damage and even cancer. Currently, applying herbs or herbal derivatives in the prevention and therapy of acute and chronic liver injury receive numerous attentions since they hold great potentials as food supplements in the treatment strategy of liver injuries. There were two major hypotheses of this current work namely: a)In CCl4-inducedacute liver injury animal model, whether pre-treatment with garlic derived S-allylmercaptocysteine (SAMC)or Wolfberry derived Lycium barbarum polysaccharides (LBP)could reduce liver injury, oxidative stress and inflammation partly through a NF-κB-dependent pathway. SAMC or LBP could also promote liver regeneration after acute damage. b)In non-alcoholic steatohepatitis (NASH)-induced chronic liver injury animal model, whether administration of SAMC or LBP along with high-fat diet induction could attenuate liver injury, lipid metabolism dysfunction, fibrosis, oxidative stress, inflammation, apoptosis and transcription factors activities in the liver. In this study, SAMC and LBP were applied in a carbon tetrachloride (CCl4) induced mice acute liver injury model and a high-fat diet induced non-alcoholic steatohepatitis model. In the acute model, an eight-hour CCl4treatment induced severe acute liver injury. Pre-treatment with SAMC or LBP (1) attenuated hepatic histological injury; (2) reduced serum ALT level; (3) ameliorated oxidative stress; (4) reduced expression of inflammatory mediators and chemokines; (5) promoted liver regeneration; and (6) decreased NF-κB activity. Vehicle-treated SAMC or LBP did not exhibit obvious adverse effects on healthy mice. In the chronic NASH model, when compared with control rats, NASH rats showed typical clinical features of human NASH patients, including increased liver injury, lipid content, oxidative stress, inflammation, and apoptosis. In comparison, SAMC or LBP co-treated NASH rats showed (1) reduced fat accumulation, cellular necrosis, collagen formation, as well as reduced serum ALT and free fatty acids levels; (2) restored insulin resistance related kinase phosphorylation status which had been altered during NASH; (3) reduced pro-fibrogenic factors; (4) restored antioxidant enzymes, as well as attenuated end-products of lipid peroxidation and NO production through a cytochrome P450 2E1-dependent pathway; (5) reduced hepatic pro-inflammatory mediators and chemokines production; (6) diminished activities of nuclear transcription factors (NF-κB and AP-1); and (7) ameliorated hepatic cellular apoptosis through a p53-dependentpathwaywhich was under the regulation of LKB1/AMPK axis and PI3K/Akt axis. In conclusion, our data demonstrated that SAMC or LBP consumption protects the liver from acute injury caused by CCl4and chronic damages caused by a high-fat diet. These effects were mainly mediated by the amelioration of hepatic oxidative stress, inflammation, and cell death. In the NASH model, SAMC or LBP also improved hepatic lipid metabolism, fibrosis, and apoptosis. Therefore, the present study proposed that both garlic and Wolfberry, which are novel hepatoprotective herbal products, can be taken as part of the dail