Preventive And Therapeutic Effect Of Network Antioxidants On The Rats With Nonalcoholic Steatohepatitis And Mechanism Study

BackgroundNonalcoholic fatty liver disease (NAFLD) is a kind of clinicopathological syndrome caused by certain reasons except alcohol and other definite factors and characterized by diffused macrovascular hepatocyte steatosis. NAFLD is a spectrum of chronic liver disease which can progress to cirrhosis and even hepatocellular carcinoma. Nonalcoholic steatohepatitis (NASH), one of NAFLD, is the critical turning point at which steatosis progresses to more advanced stages such as hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. So NASH is being paid more and more attention on. However, pathogenic mechanisms of NASH have not been clearly defined yet. The"two hit"hypothesis agrees that imbalance of oxidants and antioxidants leads to oxidative stress, resulting in lipid peroxidation which is closely related to the occurrence and development of NASH. Recently, although the foundational experiments and clinical research on the therapy for NASH have got more attention of the experts in our country and overseas, none has clearly been proved effective. So the research on pathogenesis and approaches to the treatment of NASH are urgently in need.AIMSThrough establishment of animal model of NASH in rats induced by high fat diet, changes of relative parameters of oxidative stress were monitored, aims to evaluate the role of oxidative stress in the pathogenesis of NASH. We used network antioxidants, observed the prognosis of NASH by hampering the oxidative stress injure, identified wether network antioxidants have a preventive and therapeutic effect on nonalcoholic steatohepatitis, further explored the relationship between oxidative stress and the pathogenesis of NASH.METHODSThrough successful establishment of animal model of NASH in rats induced by high fat diet, changes of liver histopathology, hepatic function, blood fat and relative parameters of oxidative stress were dynamic observed. NASH was evaluated from different angles, including morphology, biochemistry and oxidative damage, explode of the function of oxidative stress and lipid peroxidation in the pathogenesis of NASH. We tested the effect of network antioxidants (lipoic acid, coenzyme Q10, vitamin C, vitamin E, and glutathione) treatment on rats with NASH, with preventive administration or remedial administration method adopted. We observed the prognosis of NASH by using antioxidants, further evaluated the role of oxidative stress and lipid peroxidation in the pathogenesis of NASH. In addition, we compared the effect of two different administration methods, hunting the relationship between opportunity of administration and progression of NASH. Meanwhile, different treatments including metformin, fluvastatin and network oxidants were compared to reveal which one is the better therapy for NASH. RESULTS(1) The animal model of rats with NASH induced by high fat diet has been successfully established. Pathological changes in NASH model have been observed. It was revealed that oxidative stress and lipid peroxidation were involved in the pathogenesis of NASH, and were correlated with pathological changes positively. After high fat diet feeding for 8 weeks, total superoxide dismutase (SOD) activity of the model group showed descendent tendency. With aggravation of live fatty degeneration and increase of inflamation score, malondialdehyde (MDA) raised and SOD decreased. In the 12th week the level of MDA apparently increased.(2) Our data showed that network antioxidants have a preventive and therapeutic effect on nonalcoholic steatohepatitis, indicating that oxidative stress and lipid peroxidation are key factors in the pathogenesis of NASH. Serum ALT, AST, MDA and hepatic MDA, inflammation score in 8th week, 10th week and 12th week of network antioxidants-treated group were significantly lower than those of model group, while SOD activity of network antioxidants-treated group was significantly higher than that of model group.(3) Therapeutic effect of preventive administration was better than that of remedial administration. Early interventional treatment can keep high antioxidation capacity, lessen the damage of free radicals and control the progression of NASH. Serum AST, MDA and grade of histopathology in preventive administration group of network antioxidants were lower than those in remedial administration group of network antioxidants, while SOD activity in preventive administration group of network antioxidants was significantly higher than that in remedial administration group of network antioxidants.(4) Network antioxidants, metformin and fluvastatin have a therapeutic efficacy on nonalcoholic steatohepatitis. Network antioxidants seems to be superior to other groups, but these three methods have their advantages respectively. The grade of liver fatty degeneration and inflammation score of network antioxidant-treated rats were lower than those of other groups. Serum TC of fluvastatin group was the lowest in all the three therapeutic groups. The level of fasting blood glucose, serum insulin and insulin resistance index in metfomin group were lower than other groups.CONCLUSIONSNetwork antioxidants have a therapeutic efficacy on nonalcoholic steatohepatitis, which implies that oxidative stress and lipid peroxidation are closed correlated with the progression of NASH. Oxidative stress and lipid peroxidation play key roles in the pathogenesis of NASH. Network antioxidants can control lipid peroxidation effectively, hold antioxidate capacity of SOD, and keep the balance between oxidantion and antioxidantion. Early interventional treatment was proved to be more effective than remedial treatment, which tells that the treatment principle of NASH should be in accordance with early intervention. This research provided some experimental data and theoretical foundation for mechanisms and new therapeutic ways of NASH.