The Biochemical Mechanism Studied On Tetracycline-induced Nonalcoholic Fatty Liver Disease

Objective:Non-alcoholic fatty liver disease(NAFLD)is a clinical and pathological syndrome caused by the excessive accumulation of lipids in hepatic cells,not the factors that alcohol and others which clearly lead to liver damage.Available data indicate that tetracycline can promote fat accumulating and is closely associated with NAFLD and mitochondrial dysfunction,but the exact mechanism is unclear.Oxidative stress,as a main participant in the pathogenesis of NAFLD,must have been linked to tetracycline.Thus,by revealing the role of oxidative stress plays in the process of NAFLD induced by tetracycline,this study will clarify the specific biochemical mechanisms of NAFLD.Methods:(1)Using the Adult male SD rats(170-190g)to construct the NAFLD model,followed by biochemical analysis in order to investigate whether tetracycline can increase the influx of hepatic fatty acids,promote the dynamic process of oxidative stress induced by tetracycline and the related mechanisms.(2)To expose the molecular mechanism of tetracycline-induced fatty liver,combining proteomics research methods,the analysis of hepatic carbonyl proteins in NAFLD rats was performed.Results:(1)After 48 hours of treatments of tetracycline,intrahepatic triglyceride and total cholesterol were significantly increased,which in plasma decreased yet.HepG2 cells incubated with tetracycline could also increase the intracellular triglycerides.(2)With the treatment of tetracycline in SD rats,the relevant indexes of oxidative stress and hepatitis were elevated,and were positively associated with increased hepatic fatty acids.(3)The proteomics research successfully identified 26 target proteins of oxidative stress.More importantly,over half of these proteins were located in mitochondria and more than two thirds of these functional molecules did involve in metabolisms of lipids and energy.Long-chain acyl-coenzyme A dehydrogenase(ACADL),one of the oxidative stress-sensitive proteins,was the only enzyme which was located in the mitochondria and regulated β-oxidation of fatty acids.Although there was no visible difference in the ACADL’s expression between the control group and tetracycline-treated group,the treatment with tetracycline could increase the oxidative modifications of ACADL and inhibit its activity.Conclusion:(1)Tetracycline can facilitate the transport and cluster of free fatty acids to the liver,and ultimately NAFLD was developed in the rats.Currently,this is a simple and efficient method for modeling of fatty liver.(2)Tetracycline caused increasement of intrahepatic fats,and then unregulated the level of oxidative stress,aggravated the cell damages.(3)Fatty acids loading induced by tetracycline intensified intrahepatocyte oxidative stress,in turn the hepatic cells(in particular,mitochondrial)attacked by oxidative damage,which resulted in the enzymes involved in metabolisms of lipids and energy was inhibited,thereby impeded the catabolism of fatty acids and made triglycerides abnormally accumulated,finally NAFLD was developed.