Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease

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• 作者：Chunyang Du^a ; ^b ; ¹ ; ^{duchunyang55@163.com" class="auth_mail" title="E-mail the corresponding author} ; Ming Wu^a ; ^b ; ¹ ; Huan Liu^c ; ¹ ; Yunzhuo Ren^a ; ^b ; ^{renyunzhuo1978@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yunxia Du^a ; ^b ; Haijiang Wu^a ; ^b ; Jinying Wei^a ; ^b ; Chuxin Liu^c ; Fang Yao^a ; ^b ; Hui Wang^a ; ^b ; Yan Zhu^d ; Huijun Duan^a ; ^b ; ^{duanhj999@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yonghong Shi^a ; ^b ; ^{yonghongshi@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Diabetic nephropathy ; TXNIP ; Lipid accumulation ; Akt/mTOR ; SREBP-1 ; PPARα
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：79
• 期：Complete
• 页码：1-13
• 全文大小：3929 K

文摘

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-α, 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-α, 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.