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Published on: January 12, 2024
Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy
Christopher R Starr1, Assylbek Zhylkibayev2, Oleg Gorbatyuk3
1Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Abstract:
Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBPRP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice.
Insights
Carbohydrate-responsive element-binding protein (ChREBP) overexpression in the retina drives metabolic reprogramming and functional loss, contributing to diabetic retinopathy (DR) pathogenesis.
Area of Science:
- Ophthalmology and Visual Sciences
- Metabolic Research
- Molecular Biology
Background:
- Glucose-sensing transcriptional factors, ChREBP and MondoA, are key regulators of metabolic pathways but their role in ocular diseases remains understudied.
- Diabetic retinopathy (DR) is a significant complication of diabetes, characterized by progressive vision loss, with underlying molecular mechanisms requiring further elucidation.
Purpose of the Study:
- To investigate the role of ChREBP in the pathogenesis of diabetic retinopathy (DR).
- To explore the impact of ChREBP activation on retinal function and molecular changes.
Main Methods:
- Immunohistochemistry on human and mouse retinal cryosections.
- Quantitative real-time PCR (qRT-PCR) for gene expression analysis.
- Generation of constitutively active ChREBP (caChREBP) transgenic mice (caChREBPRP) for rod-specific studies.
- Retinal functional testing (electroretinography).
- Proteomic analysis using liquid chromatography-mass spectrometry (LC-MS).
- Infection of ARPE-19 cells with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) followed by global proteomics.
Main Results:
- Both ChREBP and MondoA are expressed in the retina, with elevated levels observed in DR.
- Rod-specific ChREBP activation in caChREBPRP mice led to diminished scotopic electroretinogram (ERG) amplitudes, indicating rod photoreceptor dysfunction.
- Retinal proteomic analysis revealed altered KEGG pathways related to phototransduction, amino acid metabolism, and cell adhesion.
- ChREBP overexpression induced TXNIP expression and promoted metabolic shifts towards glyoxylate signaling, sugar metabolism, and lysosomal activation in ARPE-19ChREBP cells.
Conclusions:
- ChREBP plays a significant role in the pathogenesis of diabetic retinopathy.
- Overexpression of ChREBP induces substantial metabolic reprogramming within retinal cells, leading to functional deficits and potential photoreceptor degeneration.
- Targeting ChREBP-mediated metabolic pathways may offer a novel therapeutic strategy for managing diabetic retinopathy.
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