Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy
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...
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2025-01-01
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| author | Christopher R. Starr Assylbek Zhylkibayev Oleg Gorbatyuk Alli M. Nuotio-Antar James Mobley Maria B. Grant Marina Gorbatyuk |
| author_facet | Christopher R. Starr Assylbek Zhylkibayev Oleg Gorbatyuk Alli M. Nuotio-Antar James Mobley Maria B. Grant Marina Gorbatyuk |
| author_sort | Christopher R. Starr |
| collection | DOAJ |
| description | 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 caChREBP<sup>RP</sup> 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-19<sup>ChREBP</sup>) 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 caChREBP<sup>RP</sup> 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-19<sup>ChREBP</sup> 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. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| series | Cells |
| spelling | doaj-art-618065cd548b4bd8a1fb8de10638362a2025-01-24T13:26:41ZengMDPI AGCells2073-44092025-01-0114210710.3390/cells14020107Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic RetinopathyChristopher R. Starr0Assylbek Zhylkibayev1Oleg Gorbatyuk2Alli M. Nuotio-Antar3James Mobley4Maria B. Grant5Marina Gorbatyuk6Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Biochemistry, School of Medicine, Wake Forest University, Winston Salem, NC 27101, USADepartment of Translational Neuroscience, School of Medicine, Wake Forest University, Winston Salem, NC 27101, USADepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USADepartment of Biochemistry, School of Medicine, Wake Forest University, Winston Salem, NC 27101, USAGlucose-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 caChREBP<sup>RP</sup> 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-19<sup>ChREBP</sup>) 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 caChREBP<sup>RP</sup> 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-19<sup>ChREBP</sup> 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.https://www.mdpi.com/2073-4409/14/2/107diabetic retinopathyChREBPMondoAproteomics |
| spellingShingle | Christopher R. Starr Assylbek Zhylkibayev Oleg Gorbatyuk Alli M. Nuotio-Antar James Mobley Maria B. Grant Marina Gorbatyuk Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy Cells diabetic retinopathy ChREBP MondoA proteomics |
| title | Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy |
| title_full | Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy |
| title_fullStr | Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy |
| title_full_unstemmed | Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy |
| title_short | Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy |
| title_sort | glucose sensing carbohydrate response element binding protein in the pathogenesis of diabetic retinopathy |
| topic | diabetic retinopathy ChREBP MondoA proteomics |
| url | https://www.mdpi.com/2073-4409/14/2/107 |
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