Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice.
Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice.
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DOI：
10.1038/s41598-017-01366-3
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发表时间：
2017-04-28
影响因子：
4.6
通讯作者：
Takeshita K
中科院分区：
文献类型：
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作者：
Yisireyili M;Hayashi M;Wu H;Uchida Y;Yamamoto K;Kikuchi R;Shoaib Hamrah M;Nakayama T;Wu Cheng X;Matsushita T;Nakamura S;Niwa T;Murohara T;Takeshita K
慢性应激与代谢综合征、糖尿病、高尿酸血症和血栓栓塞症密切相关，但其机制尚不清楚。我们最近报道了应激靶向内脏脂肪组织（VAT），诱导脂解，产生炎症性脂肪因子的低度炎症，代谢紊乱如胰岛素抵抗和血栓前状态。在本研究中，我们假设参与增值税黄嘌呤氧化还原酶（XOR），活性氧（ROS）和尿酸（UA）的来源在上述过程中。束缚应激导致小鼠XOR和黄嘌呤氧化酶活性上调，VAT和肝、肠内ROS积累，血清UA水平升高，NADPH氧化酶亚基上调，抗氧化酶下调。免疫组化和RT-PCR分析也表明，束缚应激诱导VAT单核细胞的积累和促炎性脂肪因子的产生，导致胰岛素敏感性降低和诱导的纤溶酶原激活物抑制剂-1和VAT组织因子。非布司他（一种强效XO抑制剂）治疗可抑制应激诱导的ROS产生和VAT炎症，从而改善血清UA水平、胰岛素敏感性和血栓形成倾向。我们的研究结果表明，应激干扰葡萄糖和UA代谢，促进血栓前状态，非布司他抑制XO可能是一种潜在的治疗应激相关疾病。
Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes. Restraint stress in mice resulted in upregulation of XOR and xanthine oxidase activity, accumulation of ROS in VAT as well as liver and intestine, increase in serum UA levels, upregulation of NADPH oxidase subunits and downregulation of antioxidant enzymes. Immunohistochemistry and RT-PCR analysis also showed that restraint stress induced VAT monocyte accumulation and proinflammatory adipokine production, resulting in reduced insulin sensitivity and induction of plasminogen activator inhibitor-1 and tissue factor in VAT. Treatment with febuxostat, a potent XO inhibitor, suppressed stress-induced ROS production and VAT inflammation, resulting in improvement of serum UA levels, insulin sensitivity, and prothrombotic tendency. Our results suggest that stress perturbs glucose and UA metabolism, and promotes prothrombotic status, and that XO inhibition by febuxostat might be a potential therapy for stress-related disorders.