Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease
Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease
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硫氧还蛋白相互作用蛋白通过 Akt/mTOR 通路调节糖尿病肾病中的脂质代谢
DOI：
10.1016/j.biocel.2016.08.006
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发表时间：
2016-10-01
影响因子：
4
通讯作者：
Shi, Yonghong
中科院分区：
文献类型：
--
作者：
Du, Chunyang;Wu, Ming;Shi, Yonghong
脂质代谢异常导致肾脏脂质堆积，与糖尿病肾病相关，但其确切机制尚不清楚。越来越多的证据表明，硫氧还蛋白相互作用蛋白参与调节细胞的糖脂代谢。在这里，我们研究了硫氧还蛋白相互作用蛋白对糖尿病肾病中脂质堆积的影响。与糖尿病野生型小鼠相比，糖尿病硫氧还蛋白相互作用蛋白基因敲除小鼠的生理生化指标有所改善。糖尿病硫氧还蛋白相互作用蛋白基因敲除小鼠的肾脏脂肪堆积、乙酰辅酶A羧基酶、脂肪酸合成酶和类固醇调节元件结合蛋白-1的表达，以及与糖尿病相关的Akt和mTOR磷酸化水平的增加在糖尿病硫氧还蛋白相互作用基因敲除小鼠中得到缓解。此外，硫氧还蛋白相互作用蛋白敲除显著增加了糖尿病肾脏中过氧化物酶体增殖物激活受体-α、酰基辅酶A氧化酶1和肉碱棕榈酰转移酶1的表达。体外实验表明，硫氧还蛋白相互作用蛋白的敲除可抑制高糖介导的脂质堆积、乙酰辅酶A羧基酶、脂肪酸合成酶和甾醇调节元件结合蛋白-1的表达，以及Akt和mTOR的激活。此外，硫氧还蛋白相互作用蛋白的下调逆转了高糖诱导的HK-2细胞中过氧化体增殖物激活受体-a、酰基辅酶A氧化酶1和肉碱棕榈酰转移酶1表达的降低。重要的是，用PI3K特异性抑制剂LY294002阻断Akt/mTOR信号通路，复制了硫氧还蛋白相互作用蛋白沉默的这些效应。综上所述，这些数据提示硫氧还蛋白相互作用蛋白缺乏症通过调节Akt/mTOR途径减轻糖尿病肾脏脂质堆积，硫氧还蛋白相互作用蛋白可能是糖尿病肾脏疾病的潜在治疗靶点。(C)2016爱思唯尔有限公司。保留所有权利。
Abnormal lipid metabolism contributes to the renal lipid accumulation, which is associated with diabetic kidney disease, but its precise mechanism remains unclear. The growing evidence demonstrates that thioredoxin-interacting protein is involved in regulating cellular glucose and lipid metabolism. Here, we investigated the effects of thioredoxin-interacting protein on lipid accumulation in diabetic kidney disease. In contrast to the diabetic wild-type mice, the physical and biochemical parameters were improved in the diabetic thioredoxin-interacting protein knockout mice. The increased renal lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, and phosphorylated Akt and mTOR associated with diabetes in wild-type mice was attenuated in diabetic thioredoxin-interacting protein knockout mice. Furthermore, thioredoxin-interacting protein knockout significantly increased the expression of peroxisome proliferator-activated receptor-alpha, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 in diabetic kidneys. In vitro experiments, using HK-2 cells, revealed that knockdown of thioredoxin-interacting protein inhibited high glucose-mediated lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, as well as activation of Akt and mTOR. Moreover, knockdown of thioredoxin-interacting protein reversed high glucose-induced reduction of peroxisome proliferator-activated receptor-a, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 expression in HK-2 cells. Importantly, blockade of Akt/mTOR signaling pathway with LY294002, a specific PI3K inhibitor, replicated these effects of thioredoxin-interacting protein silencing. Taken together, these data suggest that thioredoxin-interacting protein deficiency alleviates diabetic renal lipid accumulation through regulation of Akt/mTOR pathway, thioredoxin-interacting protein may be a potential therapeutic target for diabetic kidney disease. (C) 2016 Elsevier Ltd. All rights reserved.