Starr Christopher R, Zhylkibayev Assylbek, Gorbatyuk Oleg, Nuotio-Antar Alli M, Mobley James, Grant Maria B, Gorbatyuk Marina
Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Department of Biochemistry, School of Medicine, Wake Forest University, Winston Salem, NC 27101, USA.
Cells. 2025 Jan 13;14(2):107. doi: 10.3390/cells14020107.
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 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) 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 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 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.
葡萄糖感应转录因子ChREBP和MondoA参与了与代谢紊乱相关的脂肪生成、炎症和胰岛素信号通路；然而，针对这些蛋白质的眼部研究有限。我们旨在研究ChREBP在糖尿病视网膜病变（DR）发病机制中的潜在作用。我们使用免疫组织化学分析了糖尿病患者和小鼠的视网膜冰冻切片。进行qRT-PCR以量化基因表达。为了探究ChREBP在视杆细胞中的作用，我们构建了具有组成型活性（ca）ChREBP的caChREBP小鼠。这些小鼠接受了视网膜功能测试，随后使用LC-MS进行蛋白质组分析。此外，用表达人ChREBP的慢病毒颗粒感染ARPE-19细胞（ARPE-19-ChREBP）并进行全局蛋白质组学分析。我们的结果表明，这两种蛋白质在整个视网膜中均有表达，尽管分布模式不同：MondoA在视锥细胞中表达更突出，而ChREBP在整个视网膜中广泛表达。在DR中观察到这两种蛋白质的表达均升高。这可能导致了视杆光感受器退化，因为我们在P35时观察到caChREBP小鼠的暗视ERG振幅降低。视网膜蛋白质组学图谱显示与光转导、氨基酸代谢和细胞粘附相关的KEGG通路减少。此外，视杆细胞特异性的caChREBP诱导TXNIP表达。与视网膜蛋白质组学的改变一致，ARPE-19-ChREBP细胞表现出向乙醛酸信号增加、糖代谢和溶酶体激活的代谢转变。我们的研究表明，ChREBP过表达会导致显著的代谢重编程，引发小鼠视网膜功能丧失。
