Long-chain lipids could protect against retinal damage in diabetic retinopathy

Researchers have shown that increasing the production of long-chain fatty acids in the retina restored the integrity of tight junctions in the blood-retinal barrier, which may prevent diabetic retinopathy. By overexpressing the enzyme ELOVL4 (elongation of very long-chain fatty acids protein 4)—which is significantly reduced in the diabetic retina—the researchers increased the retina’s lipid production.

“Normalization of retinal ELOVL4 expression could prevent blood-retinal barrier dysregulation in diabetic retinopathy through an increase in very long-chain ceramides and stabilization of tight junctions,” the authors wrote in a recent study published in Diabetes.

“Our study presents an unexpected finding that the connections between cells in the retinal blood vessels contain unusual, long-chain lipids that may keep vessels from leaking, possibly preventing diabetic retinopathy from occurring,” said lead investigator Julia Busik, PhD, professor, Department of Physiology, Michigan State University, East Lansing, MI.

Although the role of ELOVL4 in skin barrier function is well known, this is the first study to demonstrate the activity of ELOVL4 in the blood-retinal barrier. ELOVL4 is an elongase, an elongation enzyme that plays a key role in fatty acid metabolism by regulating the length and eventual function of fatty acids. ELOVL4 is downregulated in diabetes and retinal ischemia reperfusion.

“ELOVL4, the highest expressed elongase in the retina, elongates extremely long fatty acids ≥C24 to produce ≥C26 very long-chain polyunsaturated fatty acids (VLCPUFA) and saturated very long-chain fatty acids (VLCFAs),” wrote the researchers. “Saturated VLCFAs are primarily incorporated into ceramides and glucosylceramides.”

“Whether a decrease in ELOVL4 and thus VLC ceramides production in the retina plays a role in blood-retinal barrier breakdown in diabetes was not known and represented a major focus of this study,” they added.

First, the researchers found that ELOVL4-mediated production of VLC ceramides—which is suppressed in diabetes—is integral for retinal endothelial barrier function. They suggested that these “good” lipids, which were previously only identified in the skin, strengthen tight junctions and could alter disease progression of diabetic retinopathy.

“It appears…that these long-chain lipids and the enzymes that produce them can protect the retina and its blood vessels,” Dr. Busik said.

Second, the researchers demonstrated that overexpression of ELOVL4 significantly prevented diabetes-induced retinal permeability and blood-retinal barrier breakdown. Using an adenoviral vector, the researchers delivered an intravitreal injection of human ELOVL4 (hELOV4) into the retinas of diabetic mice, which resulted in upregulation of hELOV4 in the retinal endothelium and prevented an increase in vascular permeability secondary to diabetes.

“Incorporating more of the long-chain lipids into the eye could potentially be a new treatment down the road and involve injections or even eye drops,” said Dr. Busik. The researchers plan to further explore such novel interventions.

This research was supported by the Juvenile Diabetes Research Foundation, National Institutes of Health National Eye Institute, and National Institute of Diabetes and Digestive and Kidney Diseases.