Hepatocyte nuclear factors 1α/4α and forkhead box A2 regulate the solute carrier 2A2 (Slc2a2) gene expression in the liver and kidney of diabetic rats

Life Sci. 2013 Nov 19;93(22):805-13. doi: 10.1016/j.lfs.2013.10.011. Epub 2013 Oct 21.


Aims: Solute carrier 2a2 (Slc2a2) gene codifies the glucose transporter GLUT2, a key protein for glucose flux in hepatocytes and renal epithelial cells of proximal tubule. In diabetes mellitus, hepatic and tubular glucose output has been related to Slc2a2/GLUT2 overexpression; and controlling the expression of this gene may be an important adjuvant way to improve glycemic homeostasis. Thus, the present study investigated transcriptional mechanisms involved in the diabetes-induced overexpression of the Slc2a2 gene.

Main methods: Hepatocyte nuclear factors 1α and 4α (HNF-1α and HNF-4α), forkhead box A2 (FOXA2), sterol regulatory element binding protein-1c (SREBP-1c) and the CCAAT-enhancer-binding protein (C/EBPβ) mRNA expression (RT-PCR) and binding activity into the Slc2a2 promoter (electrophoretic mobility assay) were analyzed in the liver and kidney of diabetic and 6-day insulin-treated diabetic rats.

Key findings: Slc2a2/GLUT2 expression increased by more than 50% (P<0.001) in the liver and kidney of diabetic rats, and 6-day insulin treatment restores these values to those observed in non-diabetic animals. Similarly, the mRNA expression and the binding activity of HNF-1α, HNF-4α and FOXA2 increased by 50 to 100% (P<0.05 to P<0.001), also returning to values of non-diabetic rats after insulin treatment. Neither the Srebf1 and Cebpb mRNA expression, nor the SREBP-1c and C/EBP-β binding activity was altered in diabetic rats.

Significance: HNF-1α, HNF-4α and FOXA2 transcriptional factors are involved in diabetes-induced overexpression of Slc2a2 gene in the liver and kidney. These data point out that these transcriptional factors are important targets to control GLUT2 expression in these tissues, which can contribute to glycemic homeostasis in diabetes.

Keywords: Diabetes; EMSA; FOXA2; GLUT2; HNFs; Nephropathy; SLC2A2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Gene Expression Regulation / drug effects
  • Glucose Transporter Type 2 / genetics*
  • Glucose Transporter Type 2 / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Hepatocyte Nuclear Factor 3-beta / genetics*
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Hepatocyte Nuclear Factor 4 / genetics*
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Insulin / pharmacology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Promoter Regions, Genetic
  • Rats
  • Rats, Wistar
  • Sterol Regulatory Element Binding Protein 1 / genetics


  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, rat
  • Foxa2 protein, rat
  • Glucose Transporter Type 2
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Hnf1a protein, rat
  • Hnf4a protein, rat
  • Insulin
  • Slc2a2 protein, rat
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Hepatocyte Nuclear Factor 3-beta