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 3

Z score–standardized mean relative abundance of FFAs, ACs, and complex lipids by carbon numbers and double bond numbers among postmortem groups.

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Z score–standardized mean relative abundance of FFAs, ACs, and complex ...
(A) Significantly higher abundant long chain ACs (C ≥ 14) in participants without diabetes and diabetics without retinopathy, higher unsaturated FFAs in participants without diabetes, and higher polyunsaturated longer-chain FAHFA in participants without diabetes, and their lower levels among diabetics with retinopathy. P values refer to significance of change in relative abundance of the corresponding lipid by increase in carbon number in ACs, by increase in unsaturated FFAs as compared with saturated FFAs in FFAs, and by increase in carbon number and number of double bonds (interaction term) in FAHFAs. (B) Significantly higher abundance of unsaturated DAGs, polyunsaturated TAGs, and PCs with higher carbon numbers in groups without diabetes and diabetics without retinopathy; however, a significantly lower abundance of unsaturated DAGs, polyunsaturated TAGs, PGs, and PCs is shown with higher carbon numbers in diabetes with retinopathy. Within each diagram, the x axis shows the number of carbons, and the y axis shows the number of double bonds. Statistical tests are based on mixed models tested the effect of study group, carbon number, and number of double bonds as the main effects and their interaction, adjusted for hypertension, hyperlipidemia, coronary artery disease, cancer, and kidney failure. P values refer to significance of change in relative abundance of the corresponding lipid by increase in number of double bonds in DAGs, and by increase in carbon number and number of double bonds (their interaction term) in TAGs, PGs, and PCs. n for both A and B is 19, 20, and 20 for participants without diabetes, diabetes with no DR, and diabetes with DR, respectively. AC, acylcarnitine; FAHFA, fatty acid ester of hydroxyl fatty acid; FFA, free fatty acid; DAG, diacylglycerol; TAG, triacylglycerol; PG, phosphatidylglycerol; PC, phosphatidylcholine; DM; diabetes mellitus; NPDR, nonproliferative diabetic retinopathy.