心理应激促进脂肪组织生成尿酸及致高尿酸血症机制

Previous studies have found that psychological stress associated with hyperuricemia. Recently, our preliminary experiment demonstrated that serum uric acid level, xanthine oxidoreductase in adipose tissue, and stress hormones including catecholamine and glucocorticoids were significantly higher in psychological stress model rat than those in control. However, its role is unknown..Thus, firstly, by population-based study, to investigate that stress hormones associated with hyperuricemia. Secondly, to clarify whether stress hormones could induce directly hyperuricemia in using spontaneous hyperuricemia model rat which was constructed by our research group. Previous studies have found that psychological stress associated with hyperuricemia. Recently, our preliminary experiment demonstrated that serum uric acid level, xanthine oxidoreductase in adipose tissue, and stress hormones including catecholamine and glucocorticoids were significantly higher in psychological stress model rat than those in control. However, its role is unknown..Thus, firstly, by population-based study, to investigate that stress hormones associated with hyperuricemia. Secondly, to clarify whether stress hormones could induce directly hyperuricemia in using spontaneous hyperuricemia model rat which was constructed by our research group. Furthermore, by experiment in vitro and vivo, to clarify whether the increasing synthesis of uric acid in adipose tissue was mediated by catecholamine through β3AR/p38MAPK/ C/EBPβ/XOR pathway activation; to clarify whether the increasing synthesis of uric acid in adipose tissue was mediated by glucocorticoids through GCR/PPARα/XOR pathway activation; further, reveal that β3AR and GCR may be an effective target for the treatment of hyperuricemia..So far, the research is still blank in the world. It is believed that the novel findings would enrich the awareness of the pathogenesis of hyperuricemia. In summary, these results may provide scientific basis for the prevention and treatment of hyperuricemia.

既往研究发现心理应激与血尿酸水平升高明显相关。本课题组发现，心理应激模型鼠血尿酸水平、应激的效应激素--儿茶酚胺和糖皮质激素显著升高，脂肪组织黄嘌呤氧化酶显著增加。心理应激促脂肪组织合成尿酸的机制不明。.为此，本课题首先通过人群研究，揭示血尿酸水平与应激相关激素关联；其次利用课题组已构建的自发高尿酸血症模型鼠（尿酸酶缺失的大鼠，尿酸不会被分解成尿囊素，呈高尿酸血症）分别采用肾上腺素和糖皮质激素处理，阐明两种应激激素与尿酸升高的因果关系。另外，通过体外研究，阐明儿茶酚胺促进脂肪组织合成尿酸的分子机制，与β3AR/p38MAPK/ C/EBPβ/XOR通路激活有关；阐明糖皮质激素促进脂肪组织合成尿酸的分子机制，与GCR/PPARα/XOR通路激活有关；进一步以β3AR和GCR为靶点进行干预，揭示其为高尿酸血症治疗靶点。.这些研究在国际上尚属空白，研究结果将丰富人们对高尿酸血症发病机制认识。

本研究发现慢性应激大鼠的血尿酸显著升高，体重增长值降低，血清应激激素（肾上腺素和地塞米松）水平升高、血脂升高。慢性应激大鼠的肝脏脂质沉积减轻、腹内白色脂肪减少。慢性应激大鼠肝脏和脂肪组织黄嘌呤氧化还原酶活性和表达量升高。转录组测序结果提示慢性应激模型中MAPK信号通路显著上调。在细胞中进行验证，应激激素处理的 HEPG2 及 3T3-L1 细胞中尿酸水平及黄嘌呤氧化酶表达量上升。双荧光素酶报告实验提示，肾上腺素通过P38/MAPK/C/EBPβ途径激活黄嘌呤氧化酶促进尿酸的合成。

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