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Int J Biochem Cell Biol. 2016 Oct;79:1-13. doi: 10.1016/j.biocel.2016.08.006. Epub 2016 Aug 3.

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

Author information

1
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: duchunyang55@163.com.
2
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
3
BGI-Shenzhen, Shenzhen, Guangdong, China.
4
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: renyunzhuo1978@163.com.
5
Laboratorical Center for Electron Microscopy, Hebei Medical University, Shijiazhuang, China.
6
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: duanhj999@163.com.
7
Department of Pathology, Hebei Medical University, Shijiazhuang, China; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. Electronic address: yonghongshi@163.com.

Abstract

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.

KEYWORDS:

Akt/mTOR; Diabetic nephropathy; Lipid accumulation; PPARα; SREBP-1; TXNIP

PMID:
27497988
DOI:
10.1016/j.biocel.2016.08.006
[Indexed for MEDLINE]

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