Bisretinoids are compounds that form in the retina throughout an individual’s lifetime. They result from the nonenzymatic reaction between retinaldehyde and photoreceptor outer segment lipid, specifically phosphatidylethanolamine (PE). These bisretinoids accumulate within retinal pigment epithelial (RPE) cells where they comprise the lipofuscin. The presence of bisretinoids has been linked to various adverse consequences for retinal health. While bisretinoids accumulate in all healthy eyes as individuals age, certain factors can influence the quantity of bisretinoids accrued. Some of these variables include the balance between bisretinoid formation in photoreceptor cells and photodegradative loss, as well as the kinetics of the visual cycle. The rate of bisretinoid formation can be modulated by factors such as the delivery of vitamin A to the RPE and the activity of key enzymes in the visual cycle, including RPE65. Mutations in various proteins of the visual cycle can also impact bisretinoid formation. Moreover, noninvasive measurements of bisretinoids have revealed differences among individuals based on gender, ethnicity, and smoking habits. One of the most concerning properties of bisretinoids is their role as photosensitizers. They have a tendency to generate reactive oxygen species, including superoxide anion and singlet oxygen, which can cause damage to retinal cells. Additionally, photooxidized bisretinoids photodegrade releasing aldehyde and dicarbonyl-bearing molecular fragments that further contribute to cellular damage.
A recent study published in the Journal of Biological Chemistry by Dr. Hye Jin Kim, Dr. Jin Zhao, Dr. Jose Walewski, and led by Professor Janet Sparrow from the Columbia University Medical Center investigated the relationship between lipid metabolism and visual health. The research team explored how dietary habits, specifically high-fat diets (HFD), may influence the formation of bisretinoids, They conducted preclinical studies in two mouse models of obesity: those induced by an HFD and those with leptin deficiency (Lep ob/ob). The authors’ findings revealed that mice on an HFD exhibited a significant increase in bisretinoid levels compared to those on a standard control diet. Specifically, the HFD-fed mice showed elevated levels of A2-GPE and A2-DHP-PE, two members of the bisretinoid family. The total measured bisretinoids were also significantly higher in the HFD-fed mice.
The researchers performed quantitative fundus imaging a noninvasive method to measure bisretinoids, and found a 35% higher level of short-wavelength fundus autofluorescence (SW-AF) in HFD-fed mice. SW-AF is known to originate from bisretinoids, which supports the link between HFD and bisretinoid accumulation. The authors also explored how age influences bisretinoid accumulation in mice. They found that older mice, whether fed an HFD or a standard diet, exhibited higher levels of bisretinoids compared to younger counterparts. This age-related increase in bisretinoid formation is consistent with previous research and highlights the cumulative nature of bisretinoid accumulation over time. To understand the mechanisms underlying the increased bisretinoid accumulation in HFD-fed mice, the authors examined plasma levels of retinol-binding protein 4 (Rbp4). Rbp4 plays a crucial role in transporting vitamin A to target cells, including the RPE. The findings showed that both HFD-fed mice and mice with leptin deficiency had elevated levels of Rbp4 in their plasma. Furthermore, they investigated whether HFDs impact the delivery of vitamin A to the retina, a potential precursor to increased bisretinoid formation. While HFDs led to higher levels of retinol in plasma, no significant changes in ocular retinoid levels were observed. This suggests that the link between HFDs and bisretinoid accumulation may not be directly related to retinoid levels in the retina.
Another important scientific question the authors answer in their study was the role of PE in bisretinoid formation. PE is a critical component of photoreceptor cell outer segments and is involved in the initial stages of bisretinoid synthesis. Their results demonstrated that mice on an HFD had a 37% higher PE content in their retina compared to those on a standard diet, emphasizing the influence of lipid metabolism on bisretinoid formation. To distinguish between diet-induced obesity and genetic obesity, the authors also examined ob/ob mice, which have leptin deficiency. Despite significant weight gain in ob/ob mice, their bisretinoid accumulation did not increase. This finding suggests that HFD-induced obesity, rather than weight gain per se, may be the key factor driving elevated bisretinoid levels.
Understanding how dietary choices and lipid metabolism impact retinal health could have significant implications for the prevention and management of retinal diseases, such as age-related macular degeneration. The new study by Professor Janet Sparrow and associates provided valuable insights into the complex relationship between lipid metabolism and retinal health. The study highlighted the role of HFDs in increasing bisretinoid accumulation, potentially contributing to retinal lipofuscin formation. These findings highlight the importance of dietary habits and lipid metabolism in the development of retinal diseases. Further research is needed to investigate in more detail the mechanisms involved and to explore potential therapeutic interventions that could mitigate the adverse effects of bisretinoid accumulation.
Kim HJ, Zhao J, Walewski JL, Sparrow JR. A high fat diet fosters elevated bisretinoids. J Biol Chem. 2023 Jun;299(6):104784. doi: 10.1016/j.jbc.2023.104784.