Dyslipidemia and Diabetic Retinopathy

Recent advances using pharmacotherapy greatly expand treatment options for diabetic
retinopathy. Intravitreal anti-VEGF immunotherapy has proven to be effective in resolving both
neovascular diabetic retinopathy (DR) and diabetic macular edema (DME)(1-5). Large clinical
studies, however, reveal that about 40% of patients do not respond to anti-VEGF therapy(1-3)
and the withdrawal of anti-VEGF after the long-term use can lead to rebound effects with
worsening of the symptoms. Importantly, anti-VEGF treatments are directed at the very late
stage in the disease, when full reversal of retinal damage is difficult. Thus, a conceptual and
technical breakthrough to identify novel targets and a strategy to cure this complication is
paramount.
Unique metabolic demands and highly specialized structure and function of the retina
dictate complex regulatory pathways to support retinal metabolism while preserving autonomy
behind the blood-retinal barrier (BRB)(6). This intricate balance is lost in a diabetic
environment(7-9). An important example of such dysregulation is the shift in the dial of
sphingolipid rheostat from protective, pro-barrier very long chain (VLC) ceramides (C≥26) to
pro-inflammatory and pro-apoptotic Short Chain (SC) ceramides (C≤24). SC ceramides in the
retina are mainly produced from sphingomyelins by acid sphingomyelinase (ASM) (10-14).
Production of VLC ceramides involves Elongation of very long chain fatty acids protein 4
(ELOVL4)-mediated synthesis of VLC saturated fatty acids that are then incorporated into
ceramides by the action of ceramide synthases (CerS)(15).
We have previously demonstrated that ASM is highly upregulated(10) and ELOVL4 is
downregulated(19) in the diabetic retina. Downregulation of ASM or upregulation of ELOVL4
were protective against diabetes-induced retinal vascular degeneration in cell culture and
animal models(10, 20).
We hypothesize that the shift in the ceramide rheostat dial from SC to VLC
ceramides will improve the outcome of diabetic retinopathy by: 1) preventing SC
ceramide-mediated pro-inflammatory and pro-apoptotic changes while 2) maintaining
VLC-ceramide barrier function.

Grant Number: 5R01EY016077-17
NIH Institute/Center: NIH
Principal Investigator: Julia Busik