Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4.
OBJECTIVE
The results of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort study revealed a strong association between dyslipidemia and the development of diabetic retinopathy. However, there are no experimental data on retinal fatty acid metabolism in diabetes. This study determined retinal-specific fatty acid metabolism in control and diabetic animals.


METHODS
Tissue gene and protein expression profiles were determined by quantitative RT-PCR and Western blot in control and streptozotocin-induced diabetic rats at 3-6 weeks of diabetes. Fatty acid profiles were assessed by reverse-phase high-performance liquid chromatography, and phospholipid analysis was performed by nano-electrospray ionization tandem mass spectrometry.


RESULTS
We found a dramatic difference between retinal and liver elongase and desaturase profiles with high elongase and low desaturase gene expression in the retina compared with liver. Elovl4, an elongase expressed in the retina but not in the liver, showed the greatest expression level among retinal elongases, followed by Elovl2, Elovl1, and Elovl6. Importantly, early-stage diabetes induced a marked decrease in retinal expression levels of Elovl4, Elovl2, and Elovl6. Diabetes-induced downregulation of retinal elongases translated into a significant decrease in total retinal docosahexaenoic acid, as well as decreased incorporation of very-long-chain polyunsaturated fatty acids (PUFAs), particularly 32:6n3, into retinal phosphatidylcholine. This decrease in n3 PUFAs was coupled with inflammatory status in diabetic retina, reflected by an increase in gene expression of proinflammatory markers interleukin-6, vascular endothelial growth factor, and intercellular adhesion molecule-1.


CONCLUSIONS
This is the first comprehensive study demonstrating diabetes-induced changes in retinal fatty acid metabolism. Normalization of retinal fatty acid levels by dietary means or/and modulating expression of elongases could represent a potential therapeutic target for diabetes-induced retinal inflammation.
Tikhonenko
Maria
M
Department of Physiology, Michigan State University, East Lansing, Michigan, USA.
Lydic
Todd A
TA
Wang
Yun
Y
Chen
Weiqin
W
Opreanu
Madalina
M
Sochacki
Andrew
A
McSorley
Kelly M
KM
Renis
Rebecca L
RL
Kern
Timothy
T
Jump
Donald B
DB
Reid
Gavin E
GE
Busik
Julia V
JV
D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D000081031:Fatty Acid Elongases; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008055:Lipids / Q000032:analysis*; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D015430:Weight Gain
D001786:Blood Glucose; D005231:Fatty Acids, Unsaturated; D008055:Lipids; D010743:Phospholipids; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases