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

• Published in: The international journal of biochemistry & cell biology Vol. 79; pp. 1 - 13
• Main Authors: Du, Chunyang, Wu, Ming, Liu, Huan, Ren, Yunzhuo, Du, Yunxia, Wu, Haijiang, Wei, Jinying, Liu, Chuxin, Yao, Fang, Wang, Hui, Zhu, Yan, Duan, Huijun, Shi, Yonghong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.2016
• Subjects: Acetyl-CoA Carboxylase - genetics; Acetyl-CoA Carboxylase - metabolism; Akt/mTOR; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Dose-Response Relationship, Drug; Fatty Acid Synthase, Type I - genetics; Fatty Acid Synthase, Type I - metabolism; Fatty Acids - metabolism; Gene Expression Regulation - drug effects; Gene Silencing; Glucose - pharmacology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Lipid accumulation; Lipid Metabolism - drug effects; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Phosphorylation - drug effects; PPAR alpha - metabolism; PPARα; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; SREBP-1; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Thioredoxins - genetics; Thioredoxins - metabolism; TOR Serine-Threonine Kinases - metabolism; TXNIP; Diabetic nephropathy; TXNIP; Lipid accumulation; PPARα; Akt/mTOR; SREBP-1
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2016.08.006

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.