Mechanism Of IMP Induced Lipid Metabolism Disorder In Elderly Db/db Mice

5’-inosine monodium(IMP)is an endogenous flavor nucleotide with stable and lasting flavor effect.According to the Hygienic Standard for the Use of Food Addictive(GB2760-1996),5’-inosine monodium salt can be used in various kinds of food according to the production needs.In daily life,this product is mixed with sodium glutamate with 5%-12%content,and its taste effect is about 8 times higher than that of sodium glutamate.It is called‘powerful monosodium glutamate’,and it is one of the main ingredients of condiments such as broad bean sauce,soy sauce and chicken essence.In organisms,IMP is the first compound synthesized in the de novo synthesis pathway of purine nucleotides,and it is the precursor of the synthesis of adenosylsuccinic acid(S-AMP),guanosine acid(GMP)and other compounds.We have studied the pharmacological function and mechanism of action of S-AMP,the next product of IMP,and found that S-AMP can form a complex with AMP-activated protein kinase(AMPK)and activate AMPK,improve the efficiency of glucose and lipid metabolism,promote lipodecomposition,and improve hyperlipidemia and other symptoms.However,no research results on IMP regulation of glucose and lipid metabolism have been published.Based on the fact that IMP has higher safety and has been widely used in food production,the preparation cost is lower,and the molecular structure similarity between IMP and AMP is higher than S-AMP,it is speculated that IMP can also improve lipid metabolism disorders after activating AMPK.Therefore,pharmacological study of IMP was carried out.We administered IMP intragastrically to 6-month-old(elderly)db/db mice at a dose of 50 mg/kg at a 24-hour interval for 8 weeks.We found that the mice lower but still higher than normal blood glucose concentration,serum triglyceride(TG),total cholesterol(TC),high-density lipoprotein(HDL),low density lipoprotein(LDL),alanine aminotransferase(ALT),alkaline phosphatase(ALP)and aspertate aminotransferase(AST)and lactate dehydrogenase(LDH)levels are increased,showed that mice hyperlipidemia has not improved,and cause serious liver damage.Surface plasmon resonance(SPR)confirmed that IMP and AMPKγ could form a stable complex.Oleic acid induced lipid accumulation of HepG2 cells of pharmacological experiments prove that IMP and AMPK after complex formation,improve the level of its phosphorylation,and then improve the mitochondrial membrane of acetyl-coa carboxylase 2(ACC2)phosphorylation level,that liver fatty acid oxidation activity increased significantly in the cell.As one of the main oxidation pathways of fatty acids is β-oxidation,a large amount of acetyl-CoA can be produced in a short time.Conformed with the results of animal experiments,with the aging of the body,the activity of the tricarboxylic acid cycle in the body is low,and the overproduced acetyl-CoA is used to synthesize TG and TC.In addition,there was no change in the expression of triglyceride lipase(ATGL),indicating that IMP could not improve the activity of lipodecomposition in the liver.TG accumulation formed the first blow in the liver.Meanwhile,TC promoted the digestion of fat in the small intestine when fatty acid oxidation was significantly increased,and fatty acids absorbed from the small intestine were mainly used to meet the metabolic needs.In this case,fatty acid oxidation reaction is in a state of long-term hyperactivity,and a large number of reactive oxygen species must be produced in liver cells to meet the requirements of fatty acid oxidation.Therefore,the liver produces oxidative stress,which leads to mitochondrial autophagy and DNA damage,so that the liver is subjected to the second blow.These findings suggest that excessive intake of IMP is the cause of aggravating liver damage caused by the double blow.Compared with the human body,IMP may also cause the same damage to the elderly with lipid metabolism disorders.Therefore,research on establishing a new food safety standard should be carried out as soon as possible.In addition,AMPK is a key target protein for the study of new lipid-lowering drugs.The results of this study demonstrated that the overactivation of AMPK in the liver of animals with low activity of the tricarboxylic acid cycle and low lipodecomposition activity is an important cause of liver oxidative stress and other injuries.With the aging of the body,there is accumulation of uric acid in the body,indicating that the accumulation of purine nucleotides,the precursor of uric acid metabolism,also occurs in the body,which may induce the above mechanism to lead to liver lesions.The results of this study provide scientific evidence to analyze the pathogenesis of fatty liver in patients with hyperuric acid and provide a new idea for drug research and development.