The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor

Sandra S Hammer, Eleni Beli, Nermin Kady, Qi Wang, Kiana Wood, Todd A Lydic, Goldis Malek, Daniel R Saban, Xiaoxin X Wang, Sugata Hazra, Moshe Levi, Julia V Busik, Maria B Grant

Research output: Contribution to journalArticle

19 Citations (Scopus)
3 Downloads (Pure)

Abstract

Diabetic retinopathy (DR) is a complication secondary to diabetes and is the number one cause of blindness among working age individuals worldwide. Despite recent therapeutic breakthroughs using pharmacotherapy, a cure for DR has yet to be realized. Several clinical trials have highlighted the vital role dyslipidemia plays in the progression of DR. Additionally, it has recently been shown that activation of Liver X receptor (LXRα/LXRβ) prevents DR in diabetic animal models. LXRs are nuclear receptors that play key roles in regulating cholesterol metabolism, fatty acid metabolism and inflammation. In this manuscript, we show insight into DR pathogenesis by demonstrating an innovative signaling axis that unifies key metabolic regulators, Sirtuin 1 and LXR, in modulating retinal cholesterol metabolism and inflammation in the diabetic retina. Expression of both regulators, Sirtuin 1 and LXR, are significantly decreased in diabetic human retinal samples and in a type 2 diabetic animal model. Additionally, activation of LXR restores reverse cholesterol transport, prevents inflammation, reduces pro-inflammatory macrophages activity and prevents the formation of diabetes-induced acellular capillaries. Taken together, the work presented in this manuscript highlights the important role lipid dysregulation plays in DR progression and offers a novel potential therapeutic target for the treatment of DR.

Original languageEnglish
Pages (from-to)181-190
Number of pages10
JournalEBioMedicine
Volume22
Early online date11 Jul 2017
DOIs
Publication statusEarly online date - 11 Jul 2017
Externally publishedYes

Bibliographical note

Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords

  • Animals
  • Cattle
  • Cells, Cultured
  • Cholesterol/metabolism
  • Diabetic Retinopathy/metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Humans
  • Liver X Receptors/metabolism
  • Mice
  • Retina/metabolism
  • Signal Transduction
  • Sirtuin 1/metabolism

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  • Cite this

    Hammer, S. S., Beli, E., Kady, N., Wang, Q., Wood, K., Lydic, T. A., Malek, G., Saban, D. R., Wang, X. X., Hazra, S., Levi, M., Busik, J. V., & Grant, M. B. (2017). The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor. EBioMedicine, 22, 181-190. https://doi.org/10.1016/j.ebiom.2017.07.008