5’-肌苷酸（Inosine Monphosphate，简称IMP）是一种内源性呈味核苷酸。IMP呈味作用稳定持久，且安全性高，中华人民共和国《食品添加剂使用卫生标准》（GB2760-1996）中对IMP的添加量并无限制：5’-肌苷酸二钠盐可在各类食品中按生产需要适量使用。日常生活中，IMP作为增鲜剂一般与谷氨酸钠混合添加，加入量约为5 %-10 %。其呈味作用比谷氨酸钠（俗称味精）增强约8倍，在业内被称为“强力味精”，是豆瓣酱、酱油、鸡精等调味品的主要成分之一。在生物体内IMP是嘌呤核苷酸从头合成通路中第一个合成的化合物，是合成腺苷酸基琥珀酸（简称S-AMP）、腺嘌呤核苷酸（AMP）、鸟苷酸（GMP）等化合物的前体。

      我们曾对嘌呤核苷酸从头合成途径中IMP的下一个产物S-AMP开展了药理学功能及作用机制研究，发现S-AMP能够与AMP活化蛋白激酶（AMPK）形成复合体并激活AMPK，提高糖脂代谢效率，促进体内脂质分解，改善高血脂等症状，但未有IMP调控糖脂代谢的研究成果发表。本课题基于IMP具有更高的安全性，在食品生产中已广泛应用，制备成本较低，由于IMP和AMP的分子结构相似度比S-AMP更高，推测IMP也具有激活AMPK后改善脂质代谢紊乱的作用，因此我们开展IMP的药理学研究。

      我们对6月龄（老年）db/db小鼠以50 mg/kg剂量灌胃给药IMP，间隔24小时给药一次，持续给药8周后发现小鼠血糖浓度降低但依然高于正常水平，血清中甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、谷丙转氨酶（ALT）、碱性磷酸酶（ALP）、谷草转氨酶（AST）和乳酸脱氢酶（LDH）含量都增加，表明小鼠的高脂血症并未得到改善，且造成严重的肝损伤。这些现象和AMPK的激动剂改善高血脂症、脂肪肝等人们的普遍认知相反，在机制研究中发现：表面等离子共振证实IMP和AMPKγ亚基可以形成稳定的复合体。对油酸诱导的脂质蓄积的HepG2细胞的药理学实验证明IMP和AMPK形成复合体后，提高其磷酸化水平，而后显著提高了线粒体膜上的乙酰辅酶A羧化酶2（ACC2）的磷酸化水平，表明肝细胞内脂肪酸氧化活性大幅度提高。同时观察到活性氧生成量比阳性药洛伐他汀显著提高，由于脂肪酸氧化的主要途径之一是β氧化，短时间内能大量生成乙酰辅酶A。和动物实验结果相印证，可以认为随着机体的衰老，体内三羧酸循环活性低下，过量产生的乙酰辅酶A被用于合成TG和TC。另外，甘油三酯脂肪酶（ATGL）表达量无变化表明IMP不能提高肝脏脂肪分解的活性，TG蓄积在肝脏内形成了第一重打击。同时脂肪酸氧化被显著提高时需要额外供给脂肪酸满足代谢需求，TC进入小肠内促进了脂肪消化，主要利用小肠中吸收的脂肪酸来满足代谢需求。这种情况下脂肪酸氧化反应处于长期亢进状态，肝细胞内必须产生大量活性氧以满足脂肪酸氧化需求，因此肝脏产生氧化应激，引发线粒体自噬、DNA损伤等让肝脏受到第二重打击。上述研究结果证明过量摄入IMP是加剧二重打击引起肝损伤的原因。相对于人体而言，IMP也可能对患有脂质代谢紊乱的老年人造成同样的损害，应尽快开展建立食品安全新标准的研究。

      此外，AMPK是用于研究降脂新药的关键作用靶点蛋白，本项研究的结果证明：三羧酸循环活性、脂肪分解活性低下的动物肝脏内AMPK过度活化是引起肝脏氧化应激等损伤的重要原因。伴随机体的衰老，体内存在尿酸蓄积，表明尿酸代谢前体的嘌呤核苷酸也在体内出现蓄积，可诱发上述机制导致肝脏病变。本项研究结果提供了分析高尿酸患者体内脂肪肝类发病机制的科学证据，为药物研发提供了新思路。

     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 AMPKγcould 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.