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Retinal de novo lipogenesis coordinates neurotrophic signaling to maintain vision
Rithwick Rajagopal, … , Fong-Fu Hsu, Clay F. Semenkovich
Rithwick Rajagopal, … , Fong-Fu Hsu, Clay F. Semenkovich
Published January 11, 2018
Citation Information: JCI Insight. 2018;3(1):e97076. https://doi.org/10.1172/jci.insight.97076.
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Research Article Metabolism Ophthalmology

Retinal de novo lipogenesis coordinates neurotrophic signaling to maintain vision

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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.

Authors

Rithwick Rajagopal, Sheng Zhang, Xiaochao Wei, Teresa Doggett, Sangeeta Adak, Jennifer Enright, Vaishali Shah, Guoyu Ling, Shiming Chen, Jun Yoshino, Fong-Fu Hsu, Clay F. Semenkovich

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Figure 1

Disruption of FAS activity in the neural retina of FASKO mice.

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Disruption of FAS activity in the neural retina of FASKO mice.
(A) Retin...
(A) Retinal message levels at various developmental stages for FAS and other lipid biosynthetic mediators (n = 4 animals/group, 2-way ANOVA). (B) FAS protein levels in homozygotes (column 2) and heterozygotes (column 3) compared with controls (columns 1 and 4) with quantitation below (n = 4/group, 1-way ANOVA). (C) FAS enzyme activity by NADPH consumption (n = 4 animals/group, 2-tailed t test). (D) FAS enzyme activity by incorporation of radiolabel (n = 4 animals/group, 2-tailed t test). (E) Total NADPH levels in whole retinal lysates (n = 3/group, 2-tailed t test). (F) Levels of free palmitate and stearate in retina (n = 6/group, 2-tailed t test). (G) Representative TUNEL staining of FAS-deficient retina and control retina (asterisks show nonspecific staining of outer segments, arrowheads show examples of TUNEL-positive nuclei included for analysis). Size bars: 12.5 μm. (H) Quantification of TUNEL staining (n = 4 animals/group, 1-way ANOVA). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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