增鲜剂5’-肌苷酸二钠恶化老龄db/db小鼠脂质代谢紊乱的分子机制

The Freshener Inosine 5’-Monophosphate Disodium Aggravates Lipid Metabolic Disorder in Elderly db/db Mice

5’-肌苷酸(inosine 5’-monophosphate,IMP)是一磷酸腺苷(adenosine 5’-monophosphate,AMP)的结构类似物。AMP能够激活AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)提高糖脂代谢效率,改善糖尿病和高血脂等症状,IMP的二钠盐是生活中常用的食品增鲜剂,但未见IMP及其二钠盐等调控糖脂代谢的研究报道。方法:选用6月龄自发性糖尿病C57/KsJ-db/db(简称db/db)小鼠为模型组,以50 mg/(kg m_(b)·d)灌胃给药IMP 8周,灌胃结束后测定小鼠生理学指标。以C57/BL/6j小鼠为正常对照组。结果:灌胃期间各组小鼠体质量无明显改变,IMP给药后db/db小鼠血糖浓度降低,但仍高于正常水平。与模型组小鼠相比,IMP给药组小鼠血清中总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白浓度和谷丙转氨酶、谷草转氨酶、碱性磷酸酶和乳酸脱氢酶活力均增加,表明IMP给药后db/db小鼠的高血脂症和肝损伤加剧恶化。分子互作研究结果证实IMP和AMPKγ亚基形成复合体可激活体内AMPK,促进脂肪酸氧化分解。体外实验证明IMP的降脂活性明显高于洛伐他汀,不仅能导致小鼠体内脂肪酸过度氧化以增加活性氧水平引起肝损伤,还能导致乙酰辅酶A蓄积而加剧脂代谢紊乱。结论:IMP可能对罹患脂质代谢紊乱的老年人造成肝损伤,加剧脂质代谢紊乱,应尽快建立食品安全新标准。

The freshener inosine 5’-monophosphate(IMP)is a structural analogue of adenosine 5’-monophosphate(AMP),which may activate AMP-activated protein kinase(AMPK)to enhance glucose and lipid metabolism,thus alleviating the symptoms of diabetes and hyperlipidemia.However,no studies have been published to determine whether IMP and its disodium salt(IMP-Na2),a commonly used freshener in our daily life,can regulate glucose and lipid metabolism.In this study,C57/KsJ-db/db(db/db)mice at the age of six months were administered intragastrically with IMP at a dose of 50 mg/(kg mb)daily for 8 weeks.Afterwards,physiological indicators of the mice were measured.C57/BL/6j mice were allocated to a normal control group.Results showed that no significant changes in mouse body mass were observed during the administration period.Blood glucose concentration in db/db mice was lowered,but it was still remarkably higher than that in normal animals.The serum levels of triglyceride,total cholesterol,high-density lipoprotein,low-density lipoprotein,alkaline phosphatase,aspartate aminotransferase,alanine aminotr ansferase,lactate dehydrogenase were increased in the IMP administered group compared to the model group,suggesting that IMP could aggravate hyperlipidemia and liver damage in mice.Molecular interaction analysis revealed that IMP and AMPKγsubunits formed a complex that could activate AMPK to promote the oxidation and decomposition of fatty acids in vivo.In vitro experiments revealed that the lipid-lowering activity of IMP was significantly higher than that of lovastatin.It not only caused fatty acid hyperoxidation in mice to increase reactive oxygen species concentration and consequently cause liver damage,but also caused the accumulation of acetyl-CoA to aggravate lipid metabolism disorders.In conclusion,IMP may cause damage to the liver of elderly people with metabolic syndrome disorders and exacerbate lipid metabolic disorders.Accordingly,new food safety standards for IMP should be established as soon as possible.