Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina

Abstract

Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin–angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin–angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.

GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

“…It is thus supposed that GSK-3β may regulates the transcription though NRF2, as NRF2 was reported as a substrate of GSK-3β kinase [ 49 ]. It has been widely documented that iron and iron metabolism could finely tune the GSK-3β and its downstream Wnt signaling [ 50 , 51 ]. Therefore, our study and these previous studies collectively suggest a backward regulation of cellular iron metabolism by GSK-3β kinase.…”

PPARα Modulation-Based Therapy in Central Nervous System Diseases

“…As expected, the therapeutic roles of fenofibric acid on CNV were abolished in Pparα knockout mice [95]. As subretinal fibrosis and disruption of retinal iron homeostasis are also pathological outcomes in AMD, the therapeutic effects of fenofibrate were examined in relation to these aspects [96,97]. Fenofibrate inhibited subretinal fibrosis in the retina of very low-density lipoprotein receptor (Vldlr) knockout mice, which is one of the models of AMD for subretinal fibrosis [96].…”

Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

“…In a pressure overload model, fenofibrate lowered plasma cholesterol and glucose levels, suggesting that it could also alleviate cardiac hypertrophy by lowering myocardial lipid and glucose metabolism 49 . Moreover, by chelating the iron, RPE cells were treated with the PPAR-agonist fenofibrate, which blocked iron-induced oxidative stress and Wnt/β-catenin signaling 50 . Activating PPAR-α transcription reportedly improves the function and energetics of the heart 51 ; hence, we evaluated the effect of ICG001 on metabolite concentration in the heart.…”