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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • 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 Metabolism* / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Oxidation-Reduction
  • PPAR alpha / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*

Substances

  • Carrier Proteins
  • Fatty Acids
  • PPAR alpha
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Txnip protein, mouse
  • Thioredoxins
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • ACACA protein, human
  • Acetyl-CoA Carboxylase
  • Glucose