Examining the role of lipid mediators in diabetic retinopathy

Abstract

Diabetic retinopathy is the most disabling complication of diabetes, affecting 65% of patients after 10 years of the disease. Current treatment options for diabetic retinopathy are highly invasive and fall short of complete amelioration of the disease. Understanding the pathogenesis of diabetic retinopathy is critical to the development of more effective treatment options. Diabetic hyperglycemia and dyslipidemia are the main metabolic insults that affect retinal degeneration in diabetes. Although the role of hyperglycemia in inducing diabetic retinopathy has been studied in detail, much less attention has been paid to dyslipidemia. Recent clinical studies have demonstrated a strong association between dyslipidemia and development of diabetic retinopathy, highlighting the importance of understanding the exact changes in retinal lipid metabolism in diabetes. This review describes what is known on the role of dyslipidemia in the development of diabetic retinopathy, with a focus on retinal-specific lipid metabolism and its dysregulation in diabetes.

Keywords: acid sphingomyelinase; cholesterol; diabetes; fatty acid; fatty acid elongase; phospholipid; retinopathy; sphingolipid.

Figure 1. De novo lipogenesis and polyunsaturated fatty acid remodeling of the Sprecher pathway

Fatty acids that accumulated in the retinal tissue are shown in boxes. The enzymes and fatty acids modified in the diabetic retina are highlighted blue.

Figure 2. Oxidized products of polyunsaturated fatty acids

Arachidonic acid products are shown in red, docosahexaenoic products are shown in yellow. The products modified in the diabetic retina are highlighted in blue boxes. HDHA: 4-hydroxy-docosahexaenoic acid; HETE: 20-hydroxyeicosatetraenoic acid; HPETE: Hydroperoxyeicosatetraenoic acid; LOX: Lipoxygenase; MOX: Monoxygenase; PUFA: Polyunsaturated fatty acid.

Figure 3. Sphingolipids synthesis and modification pathway

The enzymes and products modified in the diabetic retina are highlighted blue. CoA: Coenzyme A; S1P: Sphingosine-1-phosphate.

Figure 4. Central role of acid sphingomyelinase in the stress response in the retina

Biologically active Cer is mainly produced by the action of ASMs. Activation of ASM leads to the conversion of SM to Cer in the plasma membrane. Cer-rich membrane microdomains promote activation of signaling cascades. ASM: Acid sphingomyelinase; Cer: Ceramide; SM: Sphingomyelin.