Abstract
Purpose :
Disruptions in retinal membrane lipid homeostasis contribute to diabetic retinopathy (DR), but no current therapies are known to target these changes. In multiple mouse models of diabetes, we find that the retina engages in unusually high levels of de novo lipid biosynthesis – a pathway that regulates membrane lipids. These increases were primarily due to over-activity of one key enzyme – fatty acid synthase (FAS). Here we tested the hypotheses that FAS activity promotes DR by reconfiguring retinal plasma membrane lipids and that this pathway could represent a novel target for DR therapy.
Methods :
Using mice in models of type 1 and type 2 diabetes, or transgenic mice with elevated or reduced retinal FAS enzyme activity, we performed mass spectrometry to catalogue phospholipid species in retinal membranes derived from whole cell preparations or after gradient fractionation. After induction of either type 1 or type 2 models of diabetes in FAS gain-of-function or loss-of-function mice, we assessed DR severity by measuring dark-adapted a-wave and b-wave amplitudes, scotopic oscillatory potential (OP) timing, Müller cell reactivity, and capillary morphology.
Results :
Retinal membranes derived from type 1 and type 2 models of diabetes are depleted of very long-chain polyunsaturated fatty acids and enriched in shorter, saturated species. These changes are augmented in synaptic membrane fractions. Retinal synaptic membranes derived from FAS gain-of-function mice are also enriched in shorter chain saturated fatty acids, even in the absence of diabetes. Furthermore, compared to wild type controls, scotopic OPs become delayed in these mice at earlier time points after induction of type 2 diabetes. In contrast, diabetic mice with targeted FAS haploinsufficiency in rod photoreceptors have normal FAS activity compared to healthy controls and, accordingly, have a normal retinal synaptic membrane lipid saturation index. Moreover, diabetic mice with haploinsufficiency of FAS in rods are relatively spared from a-wave and b-wave amplitude reduction, scotopic OP delay, Müller gliosis, and capillary atrophy compared to wild-type controls.
Conclusions :
Excess rod FAS activity in diabetes is associated with increased saturation of retinal synaptic membrane lipids and is likely to be an early contributor to DR. Pharmacologic inhibition of rod FAS could be explored as a novel therapy for DR.
This is a 2020 ARVO Annual Meeting abstract.