Liver X receptor modulates diabetic retinopathy outcome in a mouse model of streptozotocin-induced diabetes

Diabetes. 2012 Dec;61(12):3270-9. doi: 10.2337/db11-1596. Epub 2012 Aug 13.


Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their dysfunction contributes to the progression of diabetic macro- and microvascular complications. Activation of "cholesterol-sensing" nuclear receptors, the liver X receptors (LXRα/LXRβ), protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. We hypothesized that LXR activation with a synthetic ligand would correct diabetes-induced EPC dysfunction and improve diabetic retinopathy. Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and in LXRα(-/-), LXRβ(-/-), and LXRα/β(-/-) mice. Retinas were evaluated for number of acellular capillaries and glial fibrillary acidic protein (GFAP) immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice showed fewer acellular capillaries and reduced GFAP expression. These mice also exhibited enhanced EPC migration and restoration of inflammatory and oxidative stress genes toward nondiabetic levels. LXRα(-/-), LXRβ(-/-), and LXRα/β(-/-) mice developed acellular capillaries and EPC dysfunction similar to the DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may represent promising pharmacologic targets for correcting retinopathy and EPC dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Benzoates / therapeutic use
  • Benzylamines / pharmacology
  • Benzylamines / therapeutic use
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Retinopathy / drug therapy
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Knockout
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Stem Cells / metabolism
  • Stem Cells / pathology


  • Benzoates
  • Benzylamines
  • GW 3965
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors