Concerted transcriptomic and lipidomic analysis highlights altered lipid metabolism in human diabetic retinopathy
Kiryakoza, Lauren   (University of Michigan-Ann Arbor)
Mentor: Fort, Patrice
Diabetic retinopathy remains the leading threat to vision in the working-age population. While not fully understood, the pathophysiology is recognized to involve damage to the neurovascular unit through various processes, including inflammation, vascular damage, neuronal dysfunction, and metabolic dysregulation. Specifically, the role of altered lipid metabolism in diabetic retinopathy is under active investigation; however, largely through the use of animal models. We hypothesize that alterations in lipid metabolism contribute to the pathophysiology of diabetic retinopathy in humans in a regional manner. Fragments of perimacular and peripheral human retinal tissue from three groups, non-diabetic (ND), diabetic without retinopathy (D), and diabetic retinopathy (DR), underwent transcriptomic analysis using RNA sequencing and lipidomic analysis using liquid chromatography-mass spectrometry. Lipidomic analysis revealed significant (p<.05) differences in monoacylglycerols, diacylglycerols, glycerophospholipids, sphingolipids, ceramides, glycerolipids, and cholesteryl esters. Among those changes, 3 specific lipid species and their generative pathways are highlighted in this project. Cholesteryl ester species, and the transcript level of the synthesizing enzyme ACAT2 (acyl-Co-a cholesterol acyltransferase), were significantly elevated in the peripheral retina (PR) of the DR group. Interestingly, diacylglycerols (DG), especially those with more than 35 carbons, as well as the transcript level of PLPPR5 (phospholipid phosphatase related protein 5), which generates DGs from phosphatidic acid, were significantly decreased in the central retina (CR). Specific phosphatidylcholine (PC) species were significantly elevated in the D group compared to DR group, while the transcript level of the rate limiting synthesizing enzyme PCYT1B (phosphate cytidylyltransferase 1, choline, beta) was significantly increased. Differences in lipid species present, amount of lipid, and degree of unsaturation in certain species support the role of altered lipid metabolism in the pathophysiology of diabetic retinopathy. Future direction includes further characterization of involved enzymes and more detailed analysis of the lipid species present.