Acetyl-CoA carboxylase Inhibition increases RPE cell fatty acid oxidation and limits apolipoprotein efflux

Area of Science:

• Ophthalmology
• Cell Biology
• Metabolic Disease

Background:

• Drusen accumulation under the retinal pigment epithelium (RPE) is a hallmark of age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD).
• Stimulating beta-oxidation in RPE cells is hypothesized to reduce drusen formation.
• Acetyl-CoA carboxylase (ACC) inhibitors are known to stimulate beta-oxidation and reduce lipid accumulation.

Approach:

• Investigated the effects of Firsocostat, an ACC inhibitor, on RPE cells.
• Utilized 13C-labeled glucose and palmitate to probe metabolic pathways (glycolysis, Krebs cycle, fatty acid metabolism).
• Assessed RPE function via transepithelial electrical resistance (TEER) and quantified lipoprotein release.

Key Points:

• Firsocostat treatment increased fatty acid oxidation and altered lipid composition in RPE cells.
• ACC inhibition improved RPE resilience to serum-induced lipid deposition.
• Firsocostat demonstrated therapeutic potential in a Sorsby's fundus dystrophy culture model, improving morphology and TEER.

Conclusions:

• Firsocostat effectively remodels intracellular metabolism and enhances RPE resilience to lipid accumulation.
• ACC inhibition presents a promising strategy for reducing drusen in AMD patients.
• Targeting RPE metabolism with ACC inhibitors could offer a novel therapeutic avenue for retinal degenerative diseases.