Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy
Patrice E. Fort, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Yang Shan, Helen C. Looker, Robert G. Nelson, Matthias Kretzler, George Michailidis, Jerome E. Roger, Thomas W. Gardner, Steven F. Abcouwer, Subramaniam Pennathur, Farsad Afshinnia
Patrice E. Fort, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Yang Shan, Helen C. Looker, Robert G. Nelson, Matthias Kretzler, George Michailidis, Jerome E. Roger, Thomas W. Gardner, Steven F. Abcouwer, Subramaniam Pennathur, Farsad Afshinnia
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Clinical Research and Public Health Ophthalmology

Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy

Abstract

BACKGROUND This study systematically investigated circulating and retinal tissue lipid determinants of human diabetic retinopathy (DR) to identify underlying lipid alterations associated with severity of DR.METHODS Retinal tissues were retrieved from postmortem human eyes, including 19 individuals without diabetes, 20 with diabetes but without DR, and 20 with diabetes and DR, for lipidomic study. In a parallel study, serum samples from 28 American Indians with type 2 diabetes from the Gila River Indian Community, including 12 without DR, 7 with mild nonproliferative DR (NPDR), and 9 with moderate NPDR, were selected. A mass-spectrometry–based lipidomic platform was used to measure serum and tissue lipids.RESULTS In the postmortem retinas, we found a graded decrease of long-chain acylcarnitines and longer-chain fatty acid ester of hydroxyl fatty acids, diacylglycerols, triacylglycerols, phosphatidylcholines, and ceramide(NS) in central retina from individuals with no diabetes to those with diabetes with DR. The American Indians’ sera also exhibited a graded decrease in circulating long-chain acylcarnitines and a graded increase in the intermediate-length saturated and monounsaturated triacylglycerols from no DR to moderate NPDR.CONCLUSION These findings suggest diminished synthesis of complex lipids and impaired mitochondrial β-oxidation of fatty acids in retinal DR, with parallel changes in circulating lipids.TRIAL REGISTRATION ClinicalTrials.gov NCT00340678.FUNDING This work was supported by NIH grants R24 DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572, P30 EY007003; The Thomas Beatson Foundation; and JDRF Center for Excellence (5-COE-2019-861-S-B).

Authors

Patrice E. Fort, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Yang Shan, Helen C. Looker, Robert G. Nelson, Matthias Kretzler, George Michailidis, Jerome E. Roger, Thomas W. Gardner, Steven F. Abcouwer, Subramaniam Pennathur, Farsad Afshinnia

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Figure 2

Comparing circulating lipids by diabetic retinopathy status.

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Comparing circulating lipids by diabetic retinopathy status. (A) Distrib...
(A) Distribution of individual ACs and TAGs by retinopathy. Within each diagram, the x axis shows the number of carbons, the y axis shows the number of double bonds, and the color codes within each cell represent the Z score standardized mean abundance of the corresponding lipid. Statistical tests were mixed models (2-tailed t test) that tested the effect of the study group, carbon number, and number of double bonds as the main effects and their interaction; they also adjusted for urine albumin/creatinine ratio, use of metformin, and insulin. P values refer to significance of change in relative abundance of the corresponding lipid by increase in carbon number in ACs, as well as by increase in carbon number and number of double bonds (their interaction term) in TAGs. n for no DR, mild, and moderate NDPR is 12, 7, and 9, respectively. (B) Components of long-chain ACs (C ≥ 14) and intermediate-length unsaturated and monounsaturated TAGs accurately predicted the group without retinopathy (100%), mild NPDR (100%), and moderate NPDR (88.9%) with an overall accuracy of 96.4%. Statistical test was canonical discriminant analysis of components of differential lipid factors. n for no DR, mild, and moderate NDPR is 12, 7, and 9, respectively. AC, acylcarnitine; CE, cholesteryl ester; DAG, diacylglycerol; TAG, triacylglycerol; PC, phosphatidylcholine; PE, phosphatidylethanolamine; LPC, lyso-PC; LPE, lyso-PE; pPE, plasmenyl-PE; SM, sphingomyelin; sFFA, saturated free fatty acid; uFFA, unsaturated FFA; Sat Monounsat, saturated and monounsaturated; Polyunsat, polyunsaturated; Intm, intermediate; NPDR, nonproliferative diabetic retinopathy.