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

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.

SUBMITTER: Hammer SS

PROVIDER: S-EPMC5552206 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Hammer Sandra S SS Beli Eleni E Kady Nermin N Wang Qi Q Wood Kiana K Lydic Todd A TA Malek Goldis G Saban Daniel R DR Wang Xiaoxin X XX Hazra Sugata S Levi Moshe M Busik Julia V JV Grant Maria B MB

EBioMedicine 20170711

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 rece ...[more]

PMID: 28774737

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Project description:BackgroundIncreasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.MethodsWe performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.ResultsOur results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).ConclusionsOur MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Dataset Information

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

Publications

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

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