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EBioMedicine. 2017 Aug;22:181-190. doi: 10.1016/j.ebiom.2017.07.008. Epub 2017 Jul 11.

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

Author information

1
Department of Physiology, Michigan State University, East Lansing, MI, United States.
2
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, United States.
3
Department of Ophthalmology, Duke University School of Medicine, Durham, NC, United States.
4
Department of Medicine, University of Colorado, Aurora, CO, United States.
5
Department of Pharmacology, University of Florida, Gainesville, FL, United States.
6
Department of Physiology, Michigan State University, East Lansing, MI, United States. Electronic address: busik@msu.edu.
7
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: mabgrant@uab.edu.

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.

KEYWORDS:

Bone marrow; Cholesterol efflux; Cholesterol metabolism; Circulating angiogenic cells; Diabetic retinopathy; Dyslipidemia; Glucose; Liver X receptor; Retinal endothelial cells; Retinal inflammation; Reverse cholesterol transport; SIRT1; Tumor necrosis factor alpha

PMID:
28774737
PMCID:
PMC5552206
DOI:
10.1016/j.ebiom.2017.07.008
[Indexed for MEDLINE]
Free PMC Article

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