High-fat diets' eye-opening impact: Study reveals link to retinal damage and bisretinoid accumulation

By Dr. Chinta SidharthanMay 8 2023

In a recent study published in the Journal of Biological Chemistry, researchers explored the association between high-fat diets and vitamin A aldehyde dysregulation, which results in bisretinoid accumulation in eyes, leading to adverse outcomes for retinal pigment epithelial and photoreceptor cells.

Study: A High Fat Diet Fosters Elevated Bisretinoids. Image Credit: Lucky Business / Shutterstock

Background

Vitamin A aldehyde adducts called bisretinoids are formed when retinaldehyde reacts with the photoreceptor outer segment lipid and accumulates naturally with age in human eyes. Bisretinoids have properties that cause adverse outcomes, such as photosensitivity, with the tendency to produce reactive oxygen forms such as singlet oxygen and superoxide anion. These reactive oxygen species further react with bisretinoids, leading to the release of molecular fragments with dicarbonyl and aldehyde.

Modulation through visual cycle kinetics can control the rate of bisretinoid accumulation. These include limiting vitamin A delivery to retinal pigment epithelial cells, mutations that reduce the activity of retinoid isomerohydrolase RPE65, and deficiencies of various visual cycle proteins such as lecithin retinol acyltransferase and 11-cis retinol dehydrogenase. Furthermore, race, gender, and smoking have shown associations with increased accumulation of bisretinoids. Given that high-fat diets increase the levels of vitamin A in the serum, it is important to examine the associations between diets rich in fats and the accumulation of bisretinoids.

About the study

In the present study, the researchers used two mice models of obesity — one with high-fat diet-induced obesity (black C57BL/6J mice) and the other with leptin deficiency-induced obesity (ob/ob)— to study the accumulation of bisretinoids. Leptin is a hormone produced in the adipose tissue that regulated food intake and energy expenditure. The same mouse model that was fed a standard diet instead of a high-fat diet was used as the control.

High performance liquid chromatography (HPLC) and ultra-performance liquid chromatography (UPLC) were used to identify peaks for pyridinium bisretinoid conjugates A2E (synthesized from vitamin A aldehyde and ethanolamine), isoA2E, A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), and A2-glycerophosphoethanolamine (A2GPE).

To account for the degradation of bisretinoids through photodegradation, comparisons were also made using albino mice that were fed the standard and the high-fat diets. Extremely old black C57BL/6J mice fed on a high-fat diet were also studied to determine the impact of age on the association between a high-fat diet and bisretinoid accumulation. Additionally, the levels of retinol-binding protein 4, retinoids, and phosphatidylethanolamine were measured.

Bisretinoid levels were also non-invasively measured through spectrophotometry using confocal fluorescence scanning laser ophthalmoscopy to quantify the short wavelength fundus autofluorescence. Additionally, the outer nuclear layer thickness was measured after the mice were sacrificed, and the eyes were enucleated to determine the viability of the photoreceptor cells.

Results

The results indicated that in the black C57BL/6J and albino mice models that were fed high-fat diets, the level of bisretinoids quantified using chromatography was higher than that in mice that were fed the standard diet. Fundus autofluorescence measurements also indicated that the bisretinoid levels were elevated in the mice fed on a high-fat diet.

Plasma levels of retinol-binding protein 4 and vitamin A were also higher in the mice fed on a high-fat diet as compared to the mice fed on a standard diet. However, the vitamin A levels in the ocular tissue were not comparatively higher. Furthermore, phosphatidylethanolamine levels were also elevated in the high-fat diet-fed mice than in the mice fed on the control diet.

In the mice model deficient in leptin, although the plasma levels of retinol-binding protein 4 were high, the bisretinoid levels in the retina had not increased. However, the decrease in outer nuclear layer thickness indicated that the viability of the photoreceptor cells was reduced in the ob/ob mice as compared to the wild-type mice.

The researchers believe that a high-fat diet can result in bisretinoid accumulation through two potential mechanisms — either through the increase in the bisretinoid fluorophores comprising the retina lipofuscin or by increasing the phosphatidylethanolamine levels in the photoreceptor cells. Other studies have also reported alterations due to a high-fat diet in the relative proportions of linoleic acid and α-linoleic acid, the precursors of omega-3 and omega-6 polyunsaturated fatty acids, respectively, in the retina.

Conclusions

To summarize, the study examined the association between high-fat diet-induced and leptin deficiency-induced obesity and the accumulation of bisretinoids in the eyes using mice models of obesity. The findings suggested that bisretinoid accumulation is associated with a high-fat diet and due to an increase in vitamin A delivery to the visual cycle.