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 4

Group discrimination by retinal lipids in a postmortem cohort.

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Group discrimination by retinal lipids in a postmortem cohort. (A and B)...
(A and B) Top differentially regulated lipids, triglycerides, phosphatidylcholine, and ACs in central retinal (A), and triglycerides and phosphatidylcholines in peripheral retina (B) discriminated 3 study groups. Analyses are based on canonical discriminant analysis with 100% accurate discrimination in central retina, and 98.3% in peripheral retina. (C and D) Statistically significant correlates of saturated and unsaturated fatty acids in the central and peripheral retina of postmortem cohort. Lipids in red indicate elevated levels; lipids in blue indicate suppressed levels; arrows in red indicate statistically significant direct correlation; arrows in blue indicate statistically significant inverse correlation. Overall saturated FFAs are inversely correlated with unsaturated FFAs. A higher abundance of unsaturated FFAs suggest shift of sFFAs toward uFFAs via action of desaturases. Direct correlation of uFFAs with complex glycerolipids suggests their higher incorporation in the construct of glycerolipids, while inverse correlation of sFFAs with complex lipids suggest their relatively lower incorporation in the construct of complex lipids. The net effect would be a relatively higher abundance of complex lipids in association with a higher abundance of uFFAs under normal physiological conditions. With progression toward diabetic retinopathy, diminished levels of uFFAs leads to diminished tissue levels of glycerophospholipids. n for all panels is 19, 20, and 20 for participants without diabetes, diabetes with no DR, and diabetes with DR, respectively. AC, acylcarnitine; sFFA, saturated free fatty acids; uFFA, unsaturated free fatty acids; DAG, diacylglycerols; PC, phosphatidylcholines; TAG, triacylglycerols.