Retinal de novo lipogenesis coordinates neurotrophic signaling to maintain vision

Abstract

Membrane lipid composition is central to the highly specialized functions of neurological tissues. In the retina, abnormal lipid metabolism causes severe forms of blindness, often through poorly understood neuronal cell death. Here, we demonstrate that deleting the de novo lipogenic enzyme fatty acid synthase (FAS) from the neural retina, but not the vascular retina, results in progressive neurodegeneration and blindness with a temporal pattern resembling rodent models of retinitis pigmentosa. Blindness was not rescued by protection from light-evoked activity; by eating a diet enriched in palmitate, the product of the FAS reaction; or by treatment with the PPARα agonist fenofibrate. Vision loss was due to aberrant synaptic structure, blunted responsiveness to glial-derived neurotrophic factor and ciliary neurotrophic factor, and eventual apoptotic cell loss. This progressive neurodegeneration was associated with decreased membrane cholesterol content, as well as loss of discrete n-3 polyunsaturated fatty acid– and saturated fatty acid–containing phospholipid species within specialized membrane microdomains. Neurotrophic signaling was restored by exogenous cholesterol delivery. These findings implicate de novo lipogenesis in neurotrophin-dependent cell survival by maintaining retinal membrane configuration and lipid composition, and they suggest that ongoing lipogenesis may be required to prevent cell death in many forms of retinopathy.

New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism

“…Moreover, using postmortem human retina samples, we recently obtained data suggesting alterations in lipid metabolism in retinas from donors with diabetic retinopathy (P. E. Fort, unpublished data), consistent with the reduction observed in BKS db/db mice [30]. The importance of these findings is highlighted by the observation that genetic deletion of the fatty acid synthase gene in the neuroretina leads to progressive neurodegeneration, with synaptic dysfunction, neuronal cell apoptosis and visual impairment [64]. As these pathological changes are also observed in diabetic retinopathy, the possibility arises that impaired lipid synthesis may contribute to the neurodegenerative effects of diabetes on the retina.…”

Pyruvate kinase M2 isoform deletion in cone photoreceptors results in age-related cone degeneration

“…FAS catalyzes the committed step in de novo lipogenesis 18 and is highly expressed in neural tissue and important for neurogenesis 19 . A recent study showed that deletion of FAS from the neural retina resulted in progressive neurodegeneration and blindness, mimicking an animal model for retinitis pigmenotsa 20 . We 4 and others 14 , 21 have shown PKM2 to be a transcriptional co-activator in gene regulation.…”

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

“…Loss of FASN in the neural retina has been shown to result in progressive neurodegeneration resembling RP in mouse models [22]. Additionally, we have previously shown that metabolic and antioxidant stress proteins were regionally expressed within the human retina, in particular the OXPHOS and TCA cycle pathways, indicating that the retinal neural network is likely sensitive to changes within the metabolic pathways that occur during disease [13].…”

“…Glucose metabolism also feeds into fatty acid synthesis and lipid metabolism pathways, which are responsible for maintaining proper membrane lipid composition in neuronal cells [21]. Disruption of lipogenesis (by deleting fatty acid synthase) in the neural retina leads to abnormal synaptic structure and apoptosis, resulting in a phenotype resembling RP [22]. Thus, loss of these key metabolic pathways and enzymes would result in abnormal nutrient and metabolite availability, and impaired visual function.…”