大豆蛋白对无症状高尿酸血症代谢作用机制的研究

Previous belief of the public is that soyfoods, which purine content is higher, can increase risk of gout and potentially precipitate acute attacks in patients with this disease. Asymptomatic hyperuricemia (HUA) is the early state of gout. If no intervention can be given to HUA, metabolic syndrome(MS) will occur. Our previous studies found that soyfoods which may actually decrease the risk of HUA are the independent protective factors of HUA and HUA combined with MS. Further, there is evidence that soyfoods may help to reduce the risk of the comorbidities associated with HUA and gout. And we also found that metabolites of patients in both HUA group and HUA combined with MS group are similar. In addition to abnormal levels of serum uric acid in HUA group, there was a change in glucose and lipid metabolic pathway. Although some researches showed that soy protein （SP）can control serum uric acid, blood glucose and lipids, the mechenism were not clear. Therefore, in this study, lack of SP （instead by casein）and low, mid and high concentration of SP will be taken as intervention. HUA rat model induced by high yeast feed and oxonic acid potassium suspension by intraperitoneal injection will be used. Animals will be divided into 6 groups. Metabonomics related technologies will be applied to find the marked metabolites which affected by SP and reversely find possible metabolic pathways involved in. Results from detection of uric acid, glucose and lipid metabolism related enzymes will combine with metabonomics analysis to observe the effect of SP on HUA rats, to judge whether SP contribute to the prevention and treatment of HUA and whether the occurrence of each component of the MS can be delayed. Renal morphology and function will be also detected to observe whether kidney is damaged. The possible regulatory mechanism of the SP on metabolism will be explored. Furthermore the optimal concentration of SP will be determined. The relationships among SP-HUA-MS will be revealed. This study has important theoretical and practical value for the early intervention and early prevention of HUA，for preventing the emergence of gout and its concurrent and reducing the occurrence and development of MS components, and for the prevention of the ultimate event of the MS like cardiovascular and cerebrovascular accidents and diabetes.

以往观点认为大豆嘌呤含量较高，其摄入会诱发高尿酸血症（HUA）。但近年研究发现大豆有助于降低HUA及其合并症发生的风险。前期研究发现，豆类是无症状HUA和HUA合并代谢综合征（MS）的独立保护因素，且HUA与HUA合并MS代谢变化相似，除尿酸水平异常外，也会出现糖、脂肪代谢改变。研究显示，大豆蛋白（SP）可影响尿酸、糖和脂肪代谢，但其机制尚未阐明。因此，本研究以SP为干预措施，HUA为靶点，应用代谢组学相关技术寻找SP作用于HUA的标志性代谢产物，并结合尿酸、糖和脂肪代谢相关酶活性及mRNA表达的检测，观察SP对HUA的防治及延缓MS发生的作用，同时观察肾脏损伤情况，寻找SP可能作用的代谢途径，探索其可能调控机制，确定SP最适作用浓度，并揭示SP-HUA-MS之间关系。这对HUA早期预防及早期干预，减少MS各组分的发生、发展及预防MS终极事件心脑血管意外和糖尿病具有重要理论意义和实用价值。

关于高尿酸血症（HUA）与大豆类食物摄入的关系一直备受热议。虽然近年研究发现大豆有助于降低HUA及其合并症代谢综合征（MS）发生的风险，而且亦有研究显示大豆蛋白（SP）可影响尿酸、糖和脂肪代谢，但其机制尚未阐明。为探索SP-HUA-MS三者之间的关系，寻找SP最佳作用浓度及其可能的代谢作用机制，本研究以SP为干预措施，HUA为靶点，将HUA模型大鼠分为SP缺乏组（D-SP）、SP低剂量组（L-SP）、SP中剂量组（M-SP）、SP高剂量组（H-SP），并设立正常大鼠阴性对照组（CON），观察SP对HUA的防治作用以及延缓MS发生的作用，同时观察其对肾脏的影响。应用代谢组学相关技术寻找SP作用于HUA的标志性代谢产物，并结合尿酸、糖和脂肪代谢相关酶的活性及其mRNA表达和蛋白表达的检测，寻找SP可能作用的代谢途径，探索其可能调控机制，确定SP最适作用浓度。本研究发现，中等浓度SP降血尿酸效果最佳，其可能机制主要有两方面。一方面是通过调节嘌呤代谢过程中的关键酶，降低尿酸的生成。中浓度SP抑制了血清XOD和GuDa的活性，提高了肝脏HGPRT的活性并抑制了肝脏XOD的活性。SP使肝脏HGPRT mRNA表达和HGPRT蛋白表达上调，使肝脏XDH蛋白表达下调。另一方面是通过促进尿尿酸的排泄，有利于尿酸排出体外，避免体内尿酸蓄积，进而降低血尿酸水平。同时，本研究提示中浓度SP具有预防HUA合并症MS部分组分发生，进而延缓MS发生和发展的作用。其机制与SP参与脂类代谢和糖代谢通路的调节有关，中浓度SP可调节机体脂类代谢及糖代谢途径中代谢产物，提高血GAPDH活性，降低血胆固醇和血糖、血胰岛素水平并改善机体胰岛素抵抗。此外，中浓度SP未见肾脏损伤及肾功能的异常。因此，中等浓度SP虽然总嘌呤含量较同等浓度酪蛋白稍高，但剂量相对安全可靠，且仍具有降低血尿酸，改善无症状HUA和预防MS的作用。本研究结果对HUA早期预防及早期干预，减少MS各组分的发生、发展及预防MS终极事件心脑血管意外和糖尿病具有重要理论意义和实用价值，为阐明大豆对无症状HUA防治的作用机制提供了理论依据。