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Rithwick Rajagopal, Sheng Zhang, Christina Oberlin, Guoyu Ling, Clay F. Semenkovich; Retinal Fatty Acid Synthase Activity is Elevated in Diabetes. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5365.
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© ARVO (1962-2015); The Authors (2016-present)
De novo lipid biosynthesis is stimulated by nutrient availability and insulin. This pathway is critical for maintenance of normal retinal function, but its role in diabetes-related pathology is poorly understood. We hypothesized that de novo lipogenesis, altered in diabetes by reduced effective insulin signaling and excess plasma glucose, is an early contributor to diabetic retinopathy. Here we test this notion by examining the function of retinal fatty acid synthase (FAS), the rate limiting enzyme in de novo lipogenesis.
In retina isolated from three models of rodent diabetes, we measured FAS expression and enzymatic activity. We developed several methods to profile lipid landscapes in whole retinal preparations and in light-membrane enriched samples from mice with diabetes. Finally, we examined the phenotype of mice with reduced retinal FAS activity.
Relative retinal FAS activity was increased by 57% in high fat-fed mice compared to chow-fed controls (P=0.001), by 31% in db/db mice compared to db/m littermates (P=0.001), and by 93% in streptozotocin-treated mice compared to vehicle-treated controls (P=0.03). In organotypic retinal explants, exogenous insulin or glucose treatment each significantly increased FAS enzyme activity. Diabetes did not change retinal FAS expression, as measured by quantitative PCR or by Western blotting. Mass spectrometry analyses of lipids extracted from whole retina and from light membrane-enriched fractions reveal distinct profiles from each preparation. Whereas homozygous depletion of retinal FAS is associated with rapid neurodegeneration, retinal FAS haploinsufficiency does not cause an observable phenotype at baseline.
In type 1 and type 2 models of rodent diabetes, FAS enzymatic activity in the retina is substantially increased over controls, whereas FAS protein and RNA levels remained unchanged. These increases may be directly caused by hyperglycemia. Comparing lipid profiles between diabetic retina and FAS mutants may identify the specific lipid residues that this change in enzyme activity impacts. Furthermore, a partial loss of function model for retinal FAS is well-suited to study the potential role of this enzyme in diabetic retinopathy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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