Fenofibrate suppresses corneal neovascularization by regulating lipid metabolism through PPARα signaling pathway

Abstract

Purpose: The purpose of this study was to explore the potential underlying mechanism of anti-vascular effects of peroxisome proliferator–activated receptor α (PPARα) agonist fenofibrate against corneal neovascularization (CNV) through the changes of lipid metabolism during CNV.Methods: A suture-induced CNV model was established and the clinical indications were evaluated from day 1 to day 7. Treatments of vehicle and fenofibrate were performed for 5 days after suture and the CNV areas were compared among the groups. The eyeballs were collected for histological analysis, malondialdehyde (MDA) measurement, terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeling (TUNEL) staining, western blot, quantitative real-time PCR (qRT-PCR) assays and immunohistochemical (IHC) staining to elucidate pathological changes and the underlying mechanism.Results: Lipi-Green staining and MDA measurement showed that lipid deposition and peroxidation were increased in the CNV cornea while the expression of long-chain acyl-coenzyme A synthetase 1 (ACSL1), carnitine palmitoyltransterase 1A(CPT1A) and medium-chain acyl-coenzyme A dehydrogenase (ACADM), which are key enzymes of fatty acid β-oxidation (FAO) and targeted genes of peroxisome proliferator-activated receptor alpha (PPARα) pathway, were decreased in CNV cornea. Fenofibrate suppressed lipid accumulation and peroxidation damage in the CNV cornea. Fenofibrate upregulated the expression levels of PPARα, ACSL1, CPT1A, and ACADM compared with vehicle group. IHC staining indicated that fenofibrate also decreased the expression of VEGFa, VEGFc, TNFα, IL1β and CD68.Conclusion: Disorder of lipid metabolism may be involved in the formation of suture-induced CNV and fenofibrate played anti-neovascularization and anti-inflammatory roles on cornea by regulating the key enzymes of lipid metabolism and ameliorating lipid peroxidation damage of cornea through PPARα signaling pathway.

Bone morphogenetic protein 4 thermosensitive hydrogel inhibits corneal neovascularization by repairing corneal epithelial apical junctional complexes

“…The length and area of CNV gradually grew with the extension of the stimulation time. On Day 5, the corneal rate-limiting barrier and tear secretion may interfere with BMP4 eye drops, preventing them from completely inhibiting CNV [ 32 , 33 ]. Poloxamer, however, exhibited histocompatibility, slow release, and good adherence.…”

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infiltration

“…Fenofibrate is a lipid-lowering drug, and several studies have found that fenofibrate has a tumor-inhibiting effect [ 34 , 35 ]. Recent studies have demonstrated that fenofibrate can inhibit corneal neovascularization by controlling important enzymes of lipid metabolism, including ACADM [ 36 ].…”

Current trends in the management of corneal neovascularization

“…Additionally, aganirsen is an antisense oligonucleotide and, unlike other agents, has FDA orphan drug designation to prevent corneal graft rejection; current phase III study results have suggested a significant inhibition of keratitis-induced corneal NV [65]. Targeted immunotherapy is a rapidly developing field with additional targets and delivery methods being considered, including nanoplatforms, atorvastatin-loaded peptide amphiphiles, and fenofibrate targeting the PPARα signaling pathway [66 ▪ ,67,68 ▪ ].…”