Type 2 diabetic mice enter a state of spontaneous hibernation-like suspended animation following accumulation of uric acid.
Type 2 diabetic mice enter a state of spontaneous hibernation-like suspended animation following accumulation of uric acid.
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2型糖尿病小鼠因尿酸积累而进入自发冬眠样假死状态
DOI：
10.1016/j.jbc.2021.101166
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhao Y;Cheng R;Zhao Y;Ge W;Yang Y;Ding Z;Xu X;Wang Z;Wu Z;Zhang J
冬眠是极端代谢低下行为的一个例子。哺乳动物如何达到这种假死状态仍不清楚。在这里，我们展示了几种 2 型糖尿病小鼠在寒冷的温度下自发进入冬眠样假死 (HLSA)。注射 ATP 的非糖尿病小鼠模拟严重低温，类似于在糖尿病小鼠中观察到的情况。我们发现尿酸（一种 ATP 代谢物）是 HLSA 进入的关键分子。尿酸与 Na+/H+ 交换蛋白的 Na+ 结合袋结合并抑制其活性，酸化细胞质并引发代谢率下降。尿酸生物合成的抑制阻止了HLSA的发生，用尿酸酶抑制剂治疗诱导的高尿酸血症小鼠可以自发地进入HLSA，类似于在2型糖尿病小鼠中观察到的情况。在大鼠和狗中，注射 ATP 会诱导 HLSA 出现类似于小鼠的可逆状态。然而，由于猪缺乏积累尿酸的能力，ATP注射无法在猪体内诱导HLSA。我们的结果提出了一种可能性，即非冬眠哺乳动物在 ATP 代谢物尿酸积累时可以自发地经历 HLSA。
Hibernation is an example of extreme hypometabolic behavior. How mammals achieve such a state of suspended animation remains unclear. Here we show that several strains of type 2 diabetic mice spontaneously enter into hibernation-like suspended animation (HLSA) in cold temperatures. Nondiabetic mice injected with ATP mimic the severe hypothermia analogous to that observed in diabetic mice. We identified that uric acid, an ATP metabolite, is a key molecular in the entry of HLSA. Uric acid binds to the Na+ binding pocket of the Na+/H+ exchanger protein and inhibits its activity, acidifying the cytoplasm and triggering a drop in metabolic rate. The suppression of uric acid biosynthesis blocks the occurrence of HLSA, and hyperuricemic mice induced by treatment with an uricase inhibitor can spontaneously enter into HLSA similar to that observed in type 2 diabetic mice. In rats and dogs, injection of ATP induces a reversible state of HLSA similar to that seen in mice. However, ATP injection fails to induce HLSA in pigs due to the lack of their ability to accumulate uric acid. Our results raise the possibility that nonhibernating mammals could spontaneously undergo HLSA upon accumulation of ATP metabolite, uric acid.
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