The Theraputic Mechanism Of KP-2 On Nonalcohol Ic Steatohepatitis

In recent years,due to the global obesity epidemic,the prevalence of nonalcoholic steatohepatitis(NASH),which is characterized by the expansion of adipose tissue,activation of oxidative stress,increased inflammatory response and varying degrees of fibrosis,has been increasing year by year.The disease increases the incidence rate and mortality of liver related diseases and increases the risk of other complications.Because of the difficulty of diagnosis,it is easy to be ignored and develop into liver cirrhosis or even liver cancer,which is harmful to human beings.So far,the main goal of NASH treatment in the world is still to improve lipid metabolism and prevent the progress of disease,but there is currently no intervention that is completely effective in the treatment of NASH.Under such circumstances,it is particularly important to develop new NASH therapy drugs with new targets and mechanisms.This article mainly focused on the theraputic mechanism of KP-2 on NASH,and established in vivo mouse model and in vitro cell model.The improving effect of KP-2 on NASH was verified by a series of technical means,and its mechanism was preliminarily explored.Secondly,KP-2,as a highly effective inhibitor of butyrylcholinesterase(BChE),can inhibit the increase of BChE activity caused by HFD in animal models.This conclusion defines the target of KP-2.In this project,the NASH animal model was constructed through induction of a high-fat diet.After high-fat feeding for three months,KP-2(10 mg/Kg)was injected intraperitoneally for one month.The experimental results are as follows:1)High-fat diet(HFD)can cause a significant increase in body weight of mice.In addition,B-ultrasound indicates that the model group has liver fat accumulation in mice,but KP-2 administration can reduce NASH-induced weight gain and reduce liver fat accumulation.2)After HE staining,compared with the control group,there are a large number of fatty vacuoles,balloon-like degeneration,severe liver damage,appeared in the liver tissue of the model group mice.However,the above liver pathological phenomena were not obvious in the KP-2 group.Furthermore,through the detection of serum transaminase,we found that the ALT and AST values in the serum of the model group increased to 2-3 times the normal level,indicating liver damage.After KP-2 was administered,the activity of transaminase was significantly reduced compared with the model group.3)The blood lipid concentration of the model group mice indicates that the NASH animal model has lipid metabolism disorders,but KP-2 can effectively reduce the increase in blood lipid concentration(including TC、TG and LDL-C)caused by HFD;At the same time,we detected the oxidative stress indicators SOD and MDA in the liver tissue of mice.It was found that the oxidative stress in the model group increased,but it was alleviated after the administration of KP-2;The expression of inflammatory factors(including IL-1β,IL-6)in this model also increased significantly,indicating an increased inflammatory response,but In the KP-2 group,the expression levels of IL-1β and IL-6 were significantly lower than those in the model group.Secondly,after fluorescent staining of lipid droplets in the cell model,it was found that the fluorescence intensity of lipid droplets in the FFA-induced cells was significantly enhanced,but the fluorescence intensity of lipid droplets in the KP-2 group was close to that in the control group.Moreover,we found that the mitochondrial aerobic metabolic capacity was reduced after FFA induction,but after KP-2 administration,this decrease was improved and the mitochondrial metabolic capacity was protected.In the cell model,we also set BChE knockout cells as the control of KP-2 group,and found that after FFA induction,the effect of KP-2 on the cells was the same as that of BChE knockout cells.This conclusion makes clear that the effect of KP-2 is achieved by inhibiting BChEIn conclusion,this paper preliminarily confirms that KP-2 can improve NASH in four aspects.The first is to affect lipid metabolism,which is mainly manifested in reducing liver fat accumulation and lipid content;The second is to protect the liver and reduce liver damage caused by NASH disease;The third is to reduce oxidative stress and reduce the increase of lipid toxicity caused by oxidative stress;The last point is to reduce the occurrence of inflammation.In addition,BChE can be used as the therapeutic target of NASH,which provides an important basis for KP-2 to treat NASH.