Cholesterol Crystals May Play Role in DR

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Researchers say they’ve deepened their understanding about the relationship between cholesterol crystal formation in the retina and diabetic retinopathy.

“This study transforms our understanding of what drives diabetic retinopathy,” said study coauthor Maria B. Grant, MD, FARVO, at the University of Alabama at Birmingham. Dr. Grant said the findings suggest that “repurposing existing cholesterol-lowering drugs to remove cholesterol crystals” in the retina may hold promise as a possible avenue to stopping disease progression.¹

Background. Studies suggest an association between diabetes and cholesterol accumulation in the retina in the form of crystals—similar to the cholesterol crystals found in atherosclerotic plaques that can form in arteries and cause heart attacks. These “hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy” in other studies, the authors wrote. So, they set out to take a closer look at the crystalline deposits, hoping their findings might help explain the mechanisms underlying retinal damage in diabetes, which to date have been unclear.

Electron microscopy. One challenge to studying cholesterol crystals is that “traditional techniques for fixing and staining tissues for microscopy involve reagents that dissolve lipids, such as cholesterol,” said lead investigator Julia V. Busik, PhD, at Michigan State University in East Lansing. This masks the potential involvement of cholesterol crystals in pathogenic mechanisms. “We used a novel methodology that does not use ethanol or organic solvents and, thus, preserves lipids in the tissues,” Dr. Busik said.

Using scanning electron microscopy, the researchers identified cholesterol crystals in donor human tissue—the same type of deposits seen on retinal images of patients with diabetes, the authors wrote. They also detected cholesterol crystals in diabetic retina from pig and mouse models.

In vitro tests. The researchers then conducted in vitro experiments to explore how cholesterol crystals affected the blood-retinal barrier breakdown in retinal endothelial and retinal pigment epithelial cells, and to see whether certain treatments affected cholesterol crystal–induced cell damage. Treatment of retinal endothelial cells with cholesterol crystals caused diabetic retina–like damage, including inflammation, cell death, and blood-retina barrier breakdown. “The fact that cholesterol crystals damage the blood-retina barrier and induce vessel leakage at an even higher degree than vascular endothelial growth factor (VEGF), a well-known barrier-disrupting agent, was a surprise,” said Dr. Busik.

Next, after treating the damaged cells with the cholesterol-lowering drug fenofibrate, the researchers noted that it significantly prevented cholesterol crystal–induced upregulation of inflammation. Additionally, treatment with the cholesterol-binding agent α-cyclodextrin dissolved cholesterol crystals, reduced retinal inflammation, and prevented diabetic retinopathy in diabetic mice. However, fenofibrate was more effective at dissolving cholesterol crystals, and it prevented breakdown of retinal cell membrane integrity and restored vascular barrier function, the researchers wrote. “The ability of α-cyclodextrin to mitigate retinal damage is proof-of-concept that clearing cholesterol crystals may stop disease progression,” said Dr. Grant. “This opens entirely new therapeutic angles for diabetic retinopathy.”

Looking ahead. Dr. Busik said that although cholesterol accumulation in the retina could lead to cholesterol crystal formation, more research is needed to understand the mechanisms underlying cholesterol crystal formation in the diabetic retina and to confirm the benefits of treatments targeting these crystals. “Cholesterol crystals may be the missing link that could unlock more effective management of this blinding complication,” she said. “We are currently looking for treatments to dissolve cholesterol crystals in the retina and examining if these can help stop disease progression and vision loss.”

—Christos Evangelou, PhD 

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1 Hammer SS et al. Diabetologia. 2023;66(9): 1705-1718.

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Relevant financial disclosures: Dr. Grant—None. Dr. Busik—None.

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